May 2022 acute hepatitis outbreak, is there a role for COVID-19 and other viruses?

Abstract

There has been an increasing number of reported cases of acute hepatitis of unknown origin in previously healthy children since first reported on March 31, 2022. This clinical syndrome is identified by jaundice and markedly elevated liver enzymes with increased aspartate transaminase and/or alanine aminotransaminase (greater than 500 IU/L). We conducted an inclusive literature review with respect to acute hepatitis outbreaks in children using the search terms acute hepatitis, outbreak, children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and adenovirus. According to the cumulative data presented in four main studies, the median age is 4 years, with a male predominance (1.3:1). Jaundice was the most common clinical manifestation (69%), followed by vomiting (63%), anorexia (52.9%), diarrhea (47.2%), abdominal pain (39%), pyrexia (33.3%), pale stool (30%), and dark urine (30%). Coryza and lethargy were reported in 16.6%, while pruritus was reported in 2% of cases. Acute liver failure was observed in 25% of cases. The exact mechanism of this acute hepatitis outbreak is still not entirely clear. Adenoviruses and SARS-CoV-2 were detected in a significant number of patients. Coinfection with adenovirus and SARS-CoV-2 could be a possible underlying mechanism. However, other possible infections and mechanisms must be considered in the pathogenesis of this condition. Acute hepatitis of unknown origin in children has been a serious problem since the start of the COVID-19 pandemic but has not yet been sufficiently addressed. Many questions remain regarding the underlying mechanisms leading to acute liver failure in children, and it is likely that extensive future research is needed.

Keywords: Acute hepatitis of unknown origin; Adenovirus; COVID-19; Children; Hepatic failure; SARS-CoV-2.

Figure 1

Reported cases of acute hepatitis syndrome of unknown aetiology in children. A: April 2022; B: May 2022. Apr: April; The UK: The United Kingdom; The USA: The United States of America.

Figure 2

Flow chart of studies included in this review.

Figure 3

Gut-liver axis. Mutual effects of the gut and liver through systemic and portal circulation and biliary enterohepatic circulation. HFD: High-fat diet; IgA: Immunoglobulin A; SCFAs: Short-chain fatty acids; TMAO: Trimethylamine N-oxide; VLDL: Very-low-density lipoprotein.

Figure 4

Effect of coronavirus disease 2019 infection on the liver as indicated by increased liver enzymes. The virus reaches the liver from the gut-liver-lung axis and may be re-shed back to the gut through the bile. These effects are mediated through the impact of hypoxia, systemic venous congestion, immune-mediated hepatic damage by inflammatory mediators induced by severe acute respiratory syndrome coronavirus-2 infection (SARS-CoV-2), the direct hepatic cytopathic effect of SARS-CoV-2, and the hepatotoxic effects of some medications used to treat SARS-CoV-2 infection such as azithromycin, chloroquine, lopinavir, ritonavir, and tocilizumab. GIT: Gastrointestinal tract; IL-6: Interleukin 6.

Figure 5

Summary of the treatment of acute hepatitis of unknown cause. AHUC: Acute hepatitis of unknown cause; GI: Gastrointestinal; HE: Hepatic encephalopathy; ICT: Increased intracranial tension.