Hepatitis (Acute) – Unknown Origin in Children

Testing Indications

There have been reports since January 2022 of increased numbers of acute hepatitis cases without known aetiology in children from the United Kingdom, Europe, Israel and the United States. Cases date back to October 2021. Hepatitis A, B, C, D and E viruses were ruled out in all of the cases and other infectious aetiologies are being investigated. There is no known association with travel. WHO issued the following release on April 23, 2022: https://www.who.int/emergencies/disease-outbreak-news/item/multi-country-acute-severe-hepatitis-of-unknown-origin-in-children

The clinical syndrome in currently identified cases is of severe acute hepatitis with markedly elevated transaminases level of >500 U/L, often with jaundice and sometimes preceded by gastrointestinal symptoms, in children up to 16 years of age. Some cases require transfer to pediatric hospitals for specialized care, including a small number that have undergone liver transplantation. As of April 25, 2022, one death has been reported in association with these incidents. Underlying causes remain unknown, but adenovirus has been identified in some cases.

Clinicians should be alert to this emerging situation, and be vigilant to infants and children presenting with signs and symptoms potentially attributable to hepatitis that may require liver function testing. These include new onset of the following:

  • Jaundice (yellow skin and/or eyes)
  • Dark urine and/or pale stools

Considering the appropriate clinical context, other symptoms that may be suggestive of hepatitis include:

  • Pruritus
  • arthralgia / myalgia
  • lethargy
  • loss of appetite
  • nausea, vomiting or abdominal pain
  • fever
PHO’s laboratory is providing testing to support the investigation of cases of hepatitis in children. Clinicians caring for children presenting with sign and symptoms that may indicate hepatitis as listed above may request the expanded testing panels described here to rule in/out infectious aetiologies.

Specimen Collection and Handling

Specimen Requirements

Test Requested Required Requisition(s) Specimen Type Minimum Volume Collection Kit

Hepatitis A, B, C, E virus serology; CMV/EBV/Parvo serology; SARS-CoV-2 serology

Serum

Preferably 5.0 ml (Minimum 3.0 ml if cannot provide more)

Blood, clotted - vacutainer tubes (SST)

Multiplex Respiratory Virus PCR; SARS-CoV-2 PCR

NP preferred; other respiratory specimens including nasal and throat swabs are acceptable

Swab in universal transport media (UTM) or media provided with kit

Virus-Respiratory Collection Kit: order# 390082

Multiplex Gastrointestinal Virus PCR

Stool (any consistency)

1.0-2.0 grams (pea size)

Virus - Enteric Kit order#: 390087

Submission and Collection Notes

1

Tests not required may be removed from the pre-filled requisitions linked above.

2

Hepatitis serology includes: Hepatitis A IgG and Hepatitis A IgM, Hepatitis B surface antigen, Hepatitis B core total Ab, Hepatitis B core IgM, Hepatitis C Antibody. If hepatitis A, B, and C are negative specimens will be sent to the National Microbiology Laboratory (NML) for hepatitis E testing. Use the pre-filled Hepatitis of Unknown Origin Requisition, which does not require the individual markers to be ordered.

3

EBV serology includes: EBV IgG (VCA, and EBNA) and VCA IgM (on all patients under 5 years old or if clinical information is documented)

4

CMV serology includes: CMV IgG and CMV IgM.

5

Parvovirus serology includes: parvovirus IgG and parvovirus IgM.

6

Multiplex Respiratory Virus PCR (MRVP) detects: influenza A, influenza A H3 subtype, influenza A H1 (pdm09) subtype, influenza B, respiratory syncytial virus (RSV A/B), parainfluenza (1 – 4), adenovirus, enterovirus, seasonal human coronavirus (OC43, 229E, NL63, HKU1), rhinovirus and human metapneumovirus.

Note: The assay detects the different RSV, parainfluenza and seasonal human coronaviruses named above but does not differentiate between them. It does not detect or cross-react with SARS-CoV-2.

7

Multiplex Gastrointestinal Virus PCR (MGVP) detects and differentiates adenovirus, rotavirus, norovirus GI and norovirus GII.

8

Both MRVP and MGVP detect a broad range of serotypes of adenovirus.

9

Adenovirus PCR on blood is recommended for all patients requiring hospitalization, and may be considered for other patients. PCR testing of blood for adenovirus is not performed at PHO’s laboratory, but is available at several tertiary hospitals in Ontario.

Limitations

Haemolyzed, icteric, lipemic or microbially contaminated serum is not recommended for testing.

Preparation Prior to Transport

Label the specimen container with the patient’s first and last name, date of collection and one other unique identifier such as the patient’s date of birth or Health Card Number. Failure to provide this information may result in rejection or testing delay.

Special Instructions

Centrifuge if using SST. Place specimen in biohazard bag and seal. Specimens should be stored at 2-8°C following collection and shipped to the PHOL on ice packs as soon as possible.

Instructions for using SST tubes are found in the document titled: LAB-SD-008, Blood Collection Using Serum Separator Tubes.

Requisitions and Kit Ordering

Test Frequency and Turnaround Time (TAT)

For turnaround time (TAT) of individual tests please refer to the specific Test Information Sheet for each test.

Serology testing of the recommended markers above is performed daily Monday to Friday. Turnaround time is up to 6 days from receipt by PHO’s laboratory.

The TAT for seasonal respiratory virus PCR and gastrointestinal virus PCR is up to 4 days after receipt by PHO’s laboratory.

Reporting

Results are reported to the ordering physician or health care provider named on the requisition.

Test Methods

Testing will be performed using multiple testing modalities to rule out known and suspect aetiologies of hepatitis.

Testing may include hepatitis A, B, C, and E, CMV, EBV, and Parvovirus serology, multiplex respiratory virus PCR, and multiplex gastrointestinal virus PCR that detect adenovirus (including a broad range of serotypes) in respiratory specimens and stool samples respectively. In addition SARS-CoV-2 PCR and serology will also be performed.

Refer to individual Test Information Sheets for more information on each test.

Algorithm

Testing is offered to support the investigation of cases of hepatitis in children. Clinicians caring for children presenting with sign and symptoms that may indicate hepatitis as listed above may request the expanded testing panels described here to rule in/out infectious aetiologies.

All adenovirus PCR positive specimens tested at PHO will undergo molecular serotyping. Adenovirus PCR positive specimens tested at other laboratories should also undergo molecular serotyping. Specimens may be forwarded to PHO’s laboratory for sequencing. Please use PHO’s laboratory General Test Requisition and indicate “adenovirus positive for molecular serotyping”. Indicate the cycle threshold (ct) value for the adenovirus PCR test. Document the patient has acute hepatitis and include relevant clinical information.

Interpretation

For test result interpretations see the test information pages for each individual test found in the Test Information Index.

Updated 28 April 2022