Diagnosis, treatment, and prevention of severe acute hepatitis of unknown etiology in children

UKHSA indicated the leading hypotheses remaining to be involved in adenovirus. However, researchers are still continuing to investigate the potential role of other viruses [7]. Nucleic acids or adenovirus antibodies were detectable in most cases. UKHSA reported that adenovirus was detected in 75% of all 131 patients, and 27 (77%) of 35 cases were  infected with adenovirus 41F [9]. Adenovirus 41F usually causes gastrointestinal infection with self-limited infection in children. Disseminated infection complicated with liver inflammation rarely occurs. Some serotypes of adenovirus can cause hepatitis in patients who have received LT or bone marrow transplantation or had ongoing chemotherapy for malignant tumors [10‐12]. Adenovirus immunohistochemistry has shown immunoreactivity in the intrasinusoidal lumen from liver samples [7], indicating that immunologic injury induced by adenovirus might be associated with this disease. A novel variant adenovirus with abnormal susceptibility to the liver might be considered to cause viral hepatitis directly [7]; however, no adenovirus particles in the liver tissue were found [2].

This outbreak occurred during the COVID-19 pandemic, and more patients were found in countries with a high burden of Omicron variant infection [13]. UKHSA reported that more than 10% of patients had SARS-CoV-2 infection on admission or prior to admission [9]. SARS-CoV-2 superantigen was supposed to be a causal mechanism of multisystem inflammatory syndrome in children [14, 15]. Both SARS-CoV-2 and adenovirus were detected in a few patients [7], and in these patients, adenovirus infection in the intestine might induce a SARS-CoV-2 superantigen reaction and cause immunopathological hepatitis [16].

Other viruses, occasionally two kinds of viruses, were detected in a few patients [7]. Based on metagenomic sequencing, adeno-associated virus 2 (AAV2) was detected in liver tissue or other samples collected from patients in several laboratories. UKHSA reported that when 19 specimens from 11 patients were detected, 9 samples from 8 patients had positive results for AAV2 [7, 9]. There are other possibilities that an unknown virus, or more than one kind of virus, may have infected the host and caused this disease [7, 9].

A drug, toxin or environmental exposure should be investigated and ruled out [7, 9].

Whole blood, serum, respiratory secretions, feces, urine or other body fluid samples can be sampled according to pathogens, and metagenomic sequencing can be performed if available.

Blood ALT, AST, total bilirubin, direct bilirubin, albumin, glutamyltransferase, prothrombin time, activated partial thrombin time, international standardized ratio (INR), fibrinogen and serum ammonia might be tested to assess the severity. C-reactive protein, procalcitonin, blood gas electrolytes, cytokines, serum ferritin, blood glucose, renal function and myocardial enzymes are helpful for evaluating related complications [2, 17].

Hepatitis viruses A, B, C, D and E, adenovirus, Epstein–Barr virus, cytomegalovirus, SARS-CoV-2, enterovirus, human herpesvirus-6 and 7, parvovirus B19, herpes simplex virus types 1 and 2, etc. Bacteria: Brucella spp, Bartonella henselae, Borrelia burgdorferi, etc. Other pathogenic microorganisms included Mycoplasma pneumoniae, Chlamydia, Leptospirosis, Plasmodium, and Entamoeba. Anti-nuclear antibodies, autoimmune hepatitis antibodies, gamma globulins, etc.

Serum ceruloplasmin, blood genetic metabolic spectrum screening, urine organic acid, etc., and whole-exome and mitochondrial gene examination are feasible if available to exclude inborn errors of metabolism-related liver injury. Blood and urine samples can be analyzed by mass spectrometry to search for possible toxic substances.

Hematoxylin and eosin staining of liver samples, adenovirus immunohistochemistry, Epstein-bar encoding region in situ hybridization, PCR or metagenomic sequencing can be performed.

Abdominal ultrasonography and magnetic resonance imaging (MRI) examinations are performed to assess liver profile, size, and bile duct structure and to identify liver and vascular anatomy and abnormalities in preparation for LT. For patients with symptoms of hepatic encephalopathy, an electroencephalogram is feasible. If necessary, head computed tomography (CT) or MRI can be used to evaluate cerebral edema and exclude cerebrovascular accidents.

According to the case definition issued by the WHO on 23 April 2022 [4], Table 1 shows diagnostic criteria for acute hepatitis of unknown etiology in children. Fig. 1 shows the diagnostic flow diagram for reference. A diagnostic flowchart is shown in fig 1. AST aspartate transaminase, ALT alanine transaminase, PT prothrombin time, APTT activated partial thrombin time, INR international standardized ratio, CBC complete blood count, CRP, c-reactive protein, PCT procalcitonin, CK creatine kinase, CT computer tomography, MRI magnetic resonance imaging, EBV Epstein–Barr virus, CMV cytomegalovirus, HHV-6 human herpesvirus-6, HHV-7 human herpesvirus-7, HSV-1 herpes simplex virus type 1, HSV-2 herpes simplex virus type 2, ANA anti-nuclear antibody

(2) Other infectious diseases ① Viruses: enterovirus, cytomegalovirus, Epstein–Barr virus, herpes simplex virus-1 and 2, human herpes virus-6 and 7, respiratory syncytial virus, parvovirus B19, influenza virus, human immunodeficiency virus, etc. [7, 9]; other pathogens: leptospirosis, plasmodium, amoeba, etc. Identification of pathogens should be based on epidemiological surveys, clinical manifestations and detection of pathogenic organisms.

(3) Medicine or toxicant-related hepatitis [18‐20] Acetaminophen is the most common cause of drug-induced hepatitis in children. Nonacetaminophen drugs, such as antibiotics, antiepileptic drugs or herbal medicines, are also related to liver damage. A history of exposure to medicine or toxicants is an important clue to diagnose. A test for serum concentrations is helpful for confirmation of identification.

(4) Autoimmune diseases Autoimmune hepatitis (AIH) [21]: the characteristics of AIH include elevated serum transaminase, hypergammaglobulinemia, and the presence of autoantibodies. The histological feature of AIH is interfacial hepatitis dominated by infiltration of lymphocytes and plasma cells. Severe cases will quickly progress to cirrhosis and liver failure. Hemophagocytic lymphohistiocytosis (HLH) [22], including familial HLH and secondary HLH. Secondary HLH can be caused by infection, tumors and other factors. In addition to increased transaminases, the diagnosis of HLH includes high persistent fever, blood cytopenia, hepatosplenomegaly, elevated ferritin, coagulation dysfunction and hemophagocytosis in bone marrow.

(5) Secondary to underlying diseases Shock, cardiac insufficiency, drug-induced hypotension and sepsis can lead to ischemic liver disease for hepatic hypoperfusion [19]. Ischemic liver disease can also be identified in Budd-Chiari syndrome and hepatic veno-occlusive disease, and imaging examination is helpful for diagnosis.

The mainstay of treatment for severe acute hepatitis of unknown etiology in children is supporting therapy [4], including adequate rest, avoiding excessive protein intake, and preventing complications. Patient consciousness, volume status, urine volume, blood electrolytes, liver function and coagulation function should be closely monitored during the entire treatment period, as should maintaining water, electrolyte and acid–base balance. Subsequent symptoms, such as hypovolemia, hypoproteinemia, gastrointestinal bleeding, infection, electrolyte imbalance, hypoglycemia, and constipation, should be actively treated to prevent serious complications, such as hepatic encephalopathy and hepatorenal syndrome.

To date, the etiology of severe acute hepatitis in children is still under investigation. For those positive for adenovirus infection, supportive care is mainly recommended. Although cidofovir has been reported to be effective against adenovirus in solid organ transplant recipients [23] and children with severe viremia [24], more studies are required to approve the benefits in immunecompetent individuals. Only case reports indicated the efficacy of ribavirin [25] for adenovirus infection.

If acute liver failure (ALF) occurs, various factors, such as decreased coagulation factor synthesis, decreased hepatic thrombopoietin, and secondary bacterial infection, may lead to coagulation disorders [26]. Prothrombin activity (PTA) and INR can be used to evaluate coagulation function in clinical practice. Newer techniques, such as thromboelastography (TEG), are also recommended [27]. Currently, there are no blood transfusion guidelines for children with ALF. Mass transfusion of plasma during treatment will confuse the INR trend of ALF. Therefore, fresh frozen plasma or platelets are not recommended for prophylactic correction of coagulation abnormalities [28]. Vitamin K should be administered when combined with vitamin K deficiency [29]; the cryoprecipitate dosage can be adjusted according to the TEG value to keep fibrinogen in the normal range [30].

Some patients have a poor prognosis, and approximately 6–10% of them need LT [5, 38]. Urgent LT is necessary for children with ALF who experience no improvement or even continuous progress after active comprehensive medical treatment [2, 6, 17, 20]. Unfortunately, there are no well-defined and universally consistent indications for LT in ALF children. The following criteria were adopted by Nadalin S et al. [17, 37]: HE ≥ grade III; INR > 2, or INR > 1.5 and associated with HE; bilirubin > 18 mg/dL; increased tendency to hypoglycemia; decreased liver size monitored by sonography (i.e., liver getting smaller because of necrosis). Irreversible serious neurologic damage, uncontrolled sepsis and uncontrolled multiorgan failure are considered contraindications for LT.

Various transplantation techniques should be applied to shorten the waiting time as much as possible in cases of ALF. Cadaveric donor LT (whole, split or reduced-size), living donor LT and even domino transplantation are applicable LT techniques [39]. With emergency LT, living donor LT may be the only option to save a patient’s life because of the lack of suitable donors [40]. Auxiliary LT can provide emergent support for native liver failure, offering a bridge to the potential spontaneous recovery of the native liver [41].