In April 2022, the UK National focal point of the International Health Regulations reported to the World Health Organization (WHO) 10 cases of severe acute hepatitis of unknown origin in children aged <10 years who had been identified in Scotland since January 2022. The affected children mainly presented with acute hepatitis with markedly elevated liver enzymes, without confirmed evidence of hepatitis A, B, C, D, or E. Later, cases of severe acute hepatitis of unknown origin surged in many European and American countries, which exceeded the past annual incidence in these regions and raised global concern. As of May 10, a total of approximately 450 pediatric cases of severe acute hepatitis of unknown origin have been reported from 21 countries and regions around the world, among which at least 18 cases required liver transplantation. Currently, no similar case has been reported in China. However, new cases of severe acute hepatitis of unknown origin have emerged in a large geographical area, and a high proportion of patients required critical care. Therefore, we specially formulated the following recommendations to standardize and guide the diagnosis and treatment of severe acute hepatitis of unknown origin at Peking Union Medical College Hospital, to get fully prepared for possible public-health events.
Of note, since no similar cases have been reported in China since January 2022, the following recommendations are mainly formulated based on current reports combined with previous clinical experience with similar patients. The working group will pay close attention to international and domestic trends to keep the recommendation updated timely.
To date, cases of severe acute hepatitis of unknown origin have been mainly reported in Europe and the United States. Most patients were aged <10 years, previously healthy, and children aged 1 to 5 years were predominantly affected. Onset of similar cases occurred in a relatively limited period, though quite sporadic without clear epidemiological association. The current data suggested a peak incidence in March 2022.
Currently, the etiology of severe acute hepatitis remains unclear. However, human adenovirus (HAdV) has been detected in serum samples of >50% of patients, and HAdV-41 Type F was detected in at least 18 cases.[1,3] In addition, some patients had concurrent coronavirus disease 2019 (COVID-19), but there is no evidence indicating its definite association with severe acute hepatitis of unknown origin.
Diagnostic process of severe acute hepatitis of unknown origin
- 1. Suspected cases: Patients showing signs of acute hepatitis, with (1) serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >500 U/L, with or without elevated bilirubin levels, and (2) exclusion of hepatitis A–E virus infections following preliminary screening; (3) Focus on children and adolescents aged ≤16 while taking adults into account as well.
- 2. Epidemiologically-related cases: Patients with acute hepatitis (not hepatitis caused by viruses A–E) of any age who have been close contacts with suspected cases.
- 3. Currently, there are no practical diagnostic criteria for this disease. However, if recommended screening criteria 1 or 2 are met, the case should be reported and the following diagnosis and treatment process should be initiated.
- 1. Epidemiological history:
- (1) History of exposure to drugs or toxins within 3 months before the disease onset.
- (2) History of contact with animals or special food.
- (3) History of vaccination against and infection with the severe acute respiratory syndrome coronavirus 2. History of other infections within 3 months.
- (4) History of contact with similar cases.
- 2. Clinical manifestations:
- The disease has an acute onset, with the most common clinical manifestations being jaundice, nausea, or vomiting, and loss of appetite. Concurrent abdominal pain or diarrhea may be observed in some patients, in addition to systemic symptoms such as fever, fatigue, and drowsiness. However, respiratory symptoms are rarely observed. Progressive disease status may be associated with increased risks of abnormal bleeding and alteration in consciousness. Patients who have progressed to liver failure may develop hepatorenal syndrome, and present with oliguria, edema, etc.
- Acute liver failure should be considered, when jaundice develops rapidly within 2 weeks of onset (daily bilirubin increase ≥17.1 μmol/L or bilirubin level >10 times the upper limit of the normal values) and progressive shrinkage of the liver is observed with or without varying degrees of kidney damage, hemorrhage, and symptoms of hepatic encephalopathy.
- 3. Family history:
- Explore the family history of possible liver diseases and autoimmune diseases.
Laboratory workup [Figure 1]
The most prominent abnormality in laboratory results is abnormal liver function, including the elevation of transaminase (ALT or AST) and bilirubin levels. Disease progression may be associated with prolonged prothrombin time and hyperammonemia.
- 1. In all cases showing signs of severe acute hepatitis, the following tests should be performed:
- (1) Complete blood counts; urine analysis; fecal analysis; liver and kidney function tests (including albumin and globulin); ammonia level; blood lipids, and coagulation functions.
- (2) Anti-HAV-IgM, HBsAg (if positive, perform the HBV-DNA test), anti-HCV-Ab (if positive, perform the HCV-RNA test), and anti-HEV-IgM.
- (3) Abdominal ultrasound examination.
- 2. Complete the following if severe acute hepatitis of unknown origin is suspected (completed separately in batches as appropriate in infants and children):
- (1) Anti-HSV1/2-IgM/IgG, CMV-DNA, EBV-DNA, anti-parvovirus B19-IgM/IgG, adenovirus typing, antibodies against Legionella pneumophila – IgM/IgG, antibodies against Mycoplasma pneumoniae and Chlamydia, Widal and Weil-Felix tests, stool culture, stool adenovirus and norovirus testing, and metagenomic sequencing of the peripheral blood.
- (2) C-reactive protein, creatine kinase, and cardiac enzymes; lymphocyte subsets, immunoglobulins and complements may be tested as appropriate.
- (3) Anti-nuclear antibody, autoimmune hepatitis antibodies (anti-smooth muscle antibody, anti-mitochondrial antibody, anti-liver-kidney microsome antibody type I, and anti-liver cytosol antibody type-I, etc.); ceruloplasmin.
- (4) Screening for heavy metals and toxins.
- (5) Imaging examinations: electrocardiogram and ultrasound of the inferior vena cava and portal vein. Magnetic resonance imaging or computed tomography may be performed when deemed necessary based on clinical judgment;
- (6) Ophthalmological consultation to determine the presence of Kayser–Fleischer (K-F) rings.
- 3. For patients in whom a clear diagnosis cannot be made after the above screening:
- (1) Collect peripheral blood samples; nasal pharyngeal swabs; and vomits, urine, and stool specimens for further etiology exploration.
- (2) If possible, liver biopsy should be performed. Biopsy specimens should be sent for routine smear examination, pathogen culture, metagenomic sequencing, and pathological examination.
- 4. Dynamic monitoring:
- The changes in the clinical conditions of newly identified patients should be closely monitored, and the frequency of indicator monitoring should be determined according to the clinical situation of the patient. For all newly identified patients, we recommend a daily repeat of complete blood counts, liver function tests and coagulation function tests for 3 consecutive days following the first visit. Thereafter, the frequency of re-examination should be determined according to the changes in clinical conditions.
As the cause of this disease remains unclear, quarantine of suspected cases is recommended during diagnosis and treatment. Objects contaminated by the feces, secretions, excrements, and blood of the patient should be thoroughly disinfected.
Once a suspected case is observed after initial assessment, the Office of Medical Administration should be informed, and diagnosis and treatment of severe hepatitis of unknown origin by a multidisciplinary team consisting of physicians from the departments of infectious diseases, pediatrics, emergency medicine, and intensive care medicine should be initiated.
- 1. General treatment:
- Bed rest to reduce physical exertion and liver burden. Energy supply should be guaranteed, with enteral nutrition as the main supply method to provide a diet with high carbohydrate, low fat, and moderate protein. For patients with insufficient oral intake, calories, fluids, vitamins, and trace elements should be supplied daily intravenously. Hypoalbuminemia should be corrected. Clinical conditions and changes in laboratory indicators such as liver function test results, electrolyte levels, acid-base equilibrium, and coagulation indicators should be closely monitored.
- 2. Treatment of liver injury and jaundice:
- Choose liver-protecting anti-inflammatory and detoxifying drugs, liver cell membrane protectors, and choleretics as appropriate according to the clinical conditions.
- 3. Correction of abnormal blood coagulation functions:
- Vitamin K1 should be supplemented intravenously when necessary (precautions should be taken to avoid allergic reactions). Blood plasma and coagulation factors should be supplemented as appropriate according to the bleeding status.
- 4. Prevention and treatment of hepatic encephalopathy:
- Appropriate protein diet should be administered to maintain free bowel movement. Lactulose and probiotics may be routinely used, and branched-chain amino acids may be supplemented as appropriate.
- 5. Prevention and treatment of hepatorenal syndrome
- Correct the status of hypovolemia, actively monitor and prompt control the potential infections, and carefully avoid nephrotoxic drugs. Hepatorenal syndrome should be considered in patients who fail to respond to the conventional combination therapy, and vasoconstrictors (terepressin or norepinephrine) infused with albumin can be used to improve the syndrome.
- 6. Bioartificial liver:
- Could be used to temporarily perform part of the liver function so that liver cells may be regenerated in acute or subacute liver failure. Bioartificial liver may also buy time for liver transplantation for patients in whom cell regeneration is not possible. Non-biological artificial liver technologies including blood perfusion, plasma adsorption, and plasma exchange can be used according to clinical evaluation.
- 7. Liver transplantation:
- For critically ill patients with poor response to internal medical treatment, liver transplantation may be considered, provided there are no contraindications.
- 8. Prevention and treatment of secondary infections:
- Attention should be paid to secondary hepatobiliary infection or spontaneous bacterial peritonitis. Based on clinical indications, empirical regimen covering Gram-negative bacilli and anaerobic bacteria may be administered, and targeted regimen should be used when further tests reveal specific pathogen evidence.
Review Experts (Arranged by alphabetical order according to surnames):
Limeng Chen (Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College [PUMCH, CAMS&PUMC]); Bin Du (Department of Administrative Office, PUMCH, CAMS&PUMC); Hongwei Fan (Department of Infectious Diseases, PUMCH, CAMS&PUMC); Ding Han (Office of the Presidents, PUMCH, CAMS&PUMC); Jing Huang (Department of Infection Control, PUMCH, CAMS&PUMC); Zhengyu Jin (Department of Radiology, PUMCH, CAMS&PUMC); Zhicheng Jing (Department of Cardiology, PUMCH, CAMS&PUMC); Xuemei Li (Department of Nephrology, PUMCH, CAMS&PUMC); Zhiyong Liang (Department of Pathology, PUMCH, CAMS&PUMC); Xiaoqing Liu (Department of Infectious Diseases, PUMCH, CAMS&PUMC); Zhengyin Liu (Department of Infectious Diseases, PUMCH, CAMS&PUMC); Yun Long (Department of Intensive Care Medicine, PUMCH, CAMS&PUMC); Xiaojun Ma (Department of Infectious Diseases, PUMCH, CAMS&PUMC); Hui Pan (Department of Medical Affairs, PUMCH, CAMS&PUMC); Xinting Sang (Department of Liver Surgery, PUMCH, CAMS&PUMC); Hongmei Song (Department of Pediatrics, PUMCH, CAMS&PUMC); Mengzhao Wang (Department of Pulmonary Critical Care Medicine PUMCH, CAMS&PUMC); Li Weng (Department of Medical Intensive Care Unit, PUMCH, CAMS&PUMC); Peixin Wu (Department of Administrative Office, PUMCH, CAMS&PUMC); Yingchun Xu (Department of Clinical Laboratory, PUMCH, CAMS&PUMC); Aiming Yang (Department of Gastrointestinal Diseases, PUMCH, CAMS&PUMC); Xiaofeng Zeng (Department of Rheumatology, PUMCH, CAMS&PUMC); Shuyang Zhang (Department of Administrative Office, PUMCH, CAMS&PUMC); Baotong Zhou (Department of Infectious Diseases, PUMCH, CAMS&PUMC); Daobin Zhou (Department of Hematology, PUMCH, CAMS&PUMC); Yicheng Zhu (Department of Neurology, PUMCH, CAMS&PUMC).
This work was funded by Key Clinical Specialties Program of Beijing, China.
Conflicts of Interest
Editor note: Wei Cao and Taisheng Li are the editors of Infectious Diseases & Immunity. The article was subject to the journal's standard procedures, with peer review handled independently by this editors and their research groups.
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