Mystery hepatitis culprit still unidentified: Timeline of a global ...

December 27, 2022

5 min read

Since April 2022, more than 1,300 children in 37 countries have developed acute severe hepatitis of unknown etiology, with the United States and the United Kingdom accounting for 65% of global cases, according to recent WHO data.

The outbreak has predominantly affected children aged younger than 10 years, with patients presenting with symptoms of diarrhea and vomiting, often preceding the development of jaundice, abdominal pain, nausea and malaise; some cases progressed to acute liver failure and required liver transplantation. As no common exposures to food or drink have been identified among these cases, viral infection has been the primary suspect.

However, none of the children were found to be infected with hepatitis A, B, C, D or E viruses, and although adenovirus infection has been repeatedly implicated — due to early cases reporting with positive tests — follow-up studies determined that fewer than half of patients have been diagnosed with adenovirus. Similarly, no link to SARS-CoV-2 infection or COVID-19 vaccination has been established, and the ultimate cause of the outbreak remains unknown.

Healio has closely followed the development of this outbreak since the initial WHO alert in April and has compiled a timeline of our coverage throughout the year. This timeline, based on data gathered and analyzed by Healio with articles written by its journalists, provides a framework for what global health experts still do not know about this puzzling hepatitis outbreak.

April 2 6 — Mystery outbreak of severe hepatitis in children prompts worldwide surveillance

The WHO has reported at least 169 cases of severe, acute hepatitis in children aged 1 month to 16 years from a dozen countries worldwide, according to a statement from the organization.

According to WHO, one child has died and 17 children have received liver transplantation as a result of the disease. As of April 21, 114 cases have been reported in the United Kingdom, followed by Spain (13), Israel (12), the United States (9), Denmark (6), Ireland (<5), the Netherlands (4), Italy (4), Norway (2), France (2), Romania (1) and Belgium (1). Read more.

April 27 — Q&A: 'The search for answers continues,' expert says about hepatitis outbreak in children

As the WHO continues its investigation into an outbreak of severe, acute hepatitis of unknown origin in children aged 1 month to 16 years, more questions than answers remain.

Healio spoke with John W. Ward, MD, director of the Coalition for Global Hepatitis Elimination, a program launched in 2019 by the Task Force for Global Health, about the outbreak and emerging data on adenovirus, which has been cited as a potential cause. Read more.

May 2 — CDC: Adenovirus should be considered in diagnosis of acute hepatitis in children

Several cases of acute, severe hepatitis in children in Alabama provided additional evidence in support of a possible link between this illness and adenovirus, according to a report published in Morbidity and Mortality Weekly Report.

"This cluster, along with recently identified possible cases in Europe, suggests that adenovirus should be considered in the differential diagnosis of acute hepatitis of unknown etiology among children," Julia M. Baker, PhD, an epidemic intelligence service officer at the CDC National Center for Immunization and Respiratory Diseases, and colleagues wrote. "Clinicians and laboratorians should be aware of possible differences in adenovirus test sensitivity for different specimen types; tests using whole blood might be more sensitive than those using plasma. Read more.

May 6 — CDC: Investigation ongoing, need time to evaluate evidence for acute hepatitis in children

The CDC reported during a media telebriefing that it is investigating cases of acute hepatitis of unknown etiology among children in the United States but warns it will take time to evaluate evidence.

The agency's investigation currently includes 109 cases of acute hepatitis in children in 25 states over the past 7 months. More than 90% of these patients were hospitalized and 14% received liver transplants; there have been five deaths. Cases have been reported in Alabama, Arizona, California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Michigan, Minnesota, Missouri, Nebraska, New York, North Carolina, North Dakota, Ohio, Pennsylvania, Puerto Rico, Tennessee, Texas, Washington and Wisconsin. Read more.

May 9 — VIDEO: Although acute hepatitis in children uncommon, parents should remain vigilant

In this Healio video exclusive, Elizabeth Fagan, MD, an independent hepatologist and consultant in Texas, discusses global concerns about cases of acute, severe hepatitis in children and what caregivers should be aware of.

According to Fagan, there are now nearly 300 cases of severe hepatitis in children worldwide, as reported by the WHO and the CDC. Symptoms include nausea, vomiting, diarrhea and general malaise, as well as progression to jaundice of the eyes and skin, dark urine and pale stools. Some children may experience respiratory problems. Read more.

June 14 — Data suggest no increase in pediatric hepatitis, adenovirus above pre-pandemic levels

Data reported in Morbidity and Mortality Weekly Report did not demonstrate an increase in pediatric hepatitis or adenovirus types 40/41 above pre-COVID-19 pandemic baseline levels.

"Following identification of pediatric hepatitis cases of unknown etiology in the United States and the United Kingdom, CDC issued a request in April 2022 for U.S. providers to report additional cases," Anita K. Kambhampati, MPH, of the division of viral diseases at the CDC National Center for Immunization and Respiratory Diseases, and colleagues wrote. "Many reported cases had test results positive for adenovirus, which is not known to cause hepatitis in immunocompetent children." Read more.

June 23 — Acute hepatitis outbreak swells to nearly 900 cases; global data shows 'mixed picture'

An outbreak of acute, severe hepatitis of unknown etiology in children has grown to 894 cases across 33 countries, according to data presented during a media briefing at the International Liver Congress in London.

"As of June 20, we now have 894 probable cases reported in 33 countries in five WHO regions," Philippa Easterbrook, MD, senior scientist at the Global HIV, Hepatitis and STI Programs at WHO headquarters in Geneva, told attendees. "Since the last WHO public communication on May 27, this represents 244 additional cases over a space of about a month. However, it's important to remember that this includes both new cases as well as retrospectively identified cases." Read more.

July 14 — Adenovirus common in pediatric hepatitis cases, but role still unclear

Although adenovirus was isolated from most children with unexplained acute hepatitis, its role in the illnesses remains unclear, according to the authors of two new studies published in The New England Journal of Medicine.

Adenovirus infection has been implicated — but not proven — as the cause of a spate of pediatric hepatitis cases with an unknown cause in multiple countries, including the United States. Read more.

August 12 — Expert: Virus pairing creates 'perfect storm' for unexplained hepatitis surge in children

New research has linked the incidence of unexplained hepatitis in pediatric patients to a pair of viruses — adenovirus type F41 and adeno-associated virus 2 — as well as potential markers of genetic mutation.

From October 2021 to July 2022, the WHO reported 1,010 probable cases of severe acute hepatitis of unknown etiology across 35 countries, including the Unites States (33% of global cases) and the United Kingdom (27%). The first cases reported were an unusual cluster of nine patients aged 2 to 11 years in Alabama. Read more.

November 7 — No 'singular definitive etiology' found for acute hepatitis outbreak in children

Although adenovirus infection has been widely implicated in an outbreak of acute, severe hepatitis in children, data presented found no "singular definitive etiology" for these cases.

"Beginning in October 2021, there were multiple clusters identified across the world of young children having a severe acute hepatitis and liver failure," Rohit Kohli, MD, division chief of gastroenterology at the Children's Hospital Los Angeles, University of Southern California, said. "Some, unfortunately, progressed to liver failure, needing liver transplantation or death, and at that time, there were alarm bells ringing at the CDC and WHO. However, beyond these local reports, we didn't understand completely what was going on as a community." Read more.

Salmonella Treatment