EDITORIAL

Acute Hepatitis in Children in 2022 — Human Adenovirus 41?

Saul J. Karpen

N Engl J Med July 13, 2022
DOI: 10.1056/NEJMe2208409

Acute hepatitis in children is certainly not new, and it can be worrisome. Successful worldwide vaccination campaigns over the past few decades have led to demonstrable improvements in public health and well-being by reducing the incidence and consequences of two viral causes — hepatitis A and B viruses. Many other viruses, some quite commonly encountered during childhood, are hepatotropic and in a minority of patients may cause illness that can escalate in severity. In these cases, liver damage manifests as elevations in serum levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), that can increase rapidly to more than 100 times the upper limit of the normal range. In these severe cases, patients’ conditions can rapidly worsen, leading to substantial impairments in liver function (e.g., coagulopathy, jaundice, and encephalopathy) that may segue to liver failure. Some patients do not have such marked elevations in aminotransferase levels and have mainly functional impairments. The majority of patients recover. However, there are limits to the remarkable regenerative capabilities of the liver, and therefore in progressive cases it is imperative that children are referred to centers that are able to provide liver transplantation.

An underlying cause of acute hepatitis is often elusive even with the application of modern gene-based and antigen-based rapid diagnostic methods. Viruses are usually presumed to be the underlying cause when a typical respiratory or gastrointestinal prodrome with fever is present. In a large series of children hospitalized with liver failure in 1999 through 2004, the most common diagnosis was “indeterminate,” in 49%,¹ and this is still the situation today. Given the young age of the patients, genetic underpinnings and (in rare cases) environmental causes are sought.^2,3 Clearly, it is crucial that we continue the search for causes of acute hepatitis, especially hepatitis leading to liver failure, so that we can effectively care for these children.

Two timely reports aiming to fill this gap — one from Birmingham, United Kingdom,⁴ and the other from Birmingham, Alabama⁵ — have now been published in the Journal. Since the original accounts of the cases from Alabama resulted in the engagement of social media, news organizations, medical societies, and epidemiologic consortia, there has been a worldwide emphasis on the recognition and reporting of acute hepatitis in children.^3,6-11 Unlike the United States, the United Kingdom uses three referral centers, including the one in Birmingham, to centralize the care of patients who may undergo liver transplantation. Kelgeri et al. report on 44 children who received treatment at the Birmingham liver center and whose conditions were consistent with the confirmed case definition of the U.K. Health Security Agency (e.g., non-A–E acute hepatitis without a metabolic, inherited or genetic, congenital, or mechanical cause in a child ≤10 years of age with a serum aminotransferase [ALT or AST] level >500 IU per liter); the median age of patients in the cohort was 4 years. The majority of the patients presented with jaundice and gastrointestinal symptoms. Six of the patients had progression to liver failure and underwent liver transplantation.

In the study from the United States, Gutierrez Sanchez et al. report on nine patients from various locations in Alabama who were treated at a children’s hospital in Birmingham and who had presenting signs and ages similar to those in the U.K. cohort, although the U.S. authors used different criteria for aminotransferase levels (>250 U per liter for ALT and >440 U per liter for AST). Three of the patients had progression to liver failure, and two of these patients underwent liver transplantation.

What is of interest here is the discovery that all 9 of the children in the U.S. case series and 27 of the 30 children who underwent molecular testing in the U.K. study tested positive for human adenovirus type 41, a finding consistent with other reports.^6,7 Serum viral loads in the patients with progression to liver failure were substantially higher than those in the patients who spontaneously recovered.

With reports like these from around the globe, is there sufficient evidence that human adenovirus 41 is a new cause of pediatric liver failure? There is not yet completely convincing evidence of a causal link, since at least in the United States there has not been an increase in reported cases of adenoviral hepatitis.⁸ Moreover, none of the histologic evaluations have revealed evidence of hepatocellular adenoviral infection, as was expected by those of us who have cared for mainly immunocompromised patients with florid adenoviral hepatitis. Adenoviral infections are exceedingly common during childhood, and human adenovirus 41 is known to cause acute gastroenteritis,¹² although not in association with liver failure. Several of the patients received cidofovir treatment, which is not known to have affected outcomes. Without evidence of adenovirus-mediated tissue damage, these studies are not yet sufficient to declare human adenovirus 41 a firm cause of acute hepatitis that can lead to liver failure. Alternatives to consider include human adenovirus 41 potentially serving as an immunologic activator or even as an innocent, readily detected bystander. Crucial unknowns must be resolved before etiologic guilt can be assigned or practice guidance regarding the initiation of therapy can be provided.

Moreover, human adenovirus was found along with other common pediatric viruses in a number of the cases (e.g., rhinovirus, enterovirus, and influenza virus) and, in the U.K. series, SARS-CoV-2. Without broader epidemiologic data on viruses in children who present to pediatricians or emergency departments for any indication, this does not seem unexpected and should minimize reflections about multiple viral causes. Similarly, appropriate studies and data are needed before speculation about pandemic-related alterations in immunologic reactivity to childhood illnesses can be supported or refuted.

Finally, no one wants to hear of a potential new virus of concern in the world these days. However, it is not at all clear that this adenoviral strain is new, of increasing incidence, or causative of acute hepatitis and pediatric liver failure, since such data have not been prospectively collected in children. These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed; these are currently being developed in Europe¹³ and in North America.¹⁰ It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children.