Adeno-associated virus type 2 in US children with acute severe hepatitis - Nature.com

Abstract

As of August 2022, clusters of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States^1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from cases in Europe and the United States^3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze samples from 16 HAdV-positive cases from October 1, 2021 to May 22, 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P<0.001) and to 0 of 30 patients with hepatitis of defined etiology (P<0.001). In controls, HAdV-41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P<0.001). Co-infections by Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P<0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

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Author information

Author notes

1. These authors contributed equally: Venice Servellita, Alicia Sotomayor Gonzalez, Daryl M. Lamson

Authors and Affiliations

1. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA

   Venice Servellita, Alicia Sotomayor Gonzalez, Abiodun Foresythe, Hee Jae Huh, Paul E. Oluniyi, Jenny Nguyen, Jessica Tan, Doug Stryke, Miriam Oseguera, Robert Blattner & Charles Y. Chiu

2. Wadsworth Center, New York State Department of Health, David Axelrod Institute, Albany, NY, USA

   Daryl M. Lamson & Kirsten St. George

3. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

   Hee Jae Huh

4. National Biodefense Analysis and Countermeasures Center (NBACC), Frederick, MD, USA

   Adam L. Bazinet, Nicholas H. Bergman, Karla Y. Garcia, Jennifer S. Goodrich, Sean P. Lovett, Kisha Parker, Diana Radune & R. Taylor Raborn

5. Federal Bureau of Investigation Laboratory Division / Scientific Response and Analysis Unit, Quantico, VA, USA

   Robert L. Bull

6. California Department of Public Health, Richmond, CA, USA

   April Hatada, Chao-Yang Pan, Kyle Rizzo, J. Bradford Bertumen, Christina Morales & Debra A. Wadford

7. Florida Department of Health, Tallahassee, USA

   Rayah Jaber & Natalia Cano

8. Illinois Department of Public Health, Chicago, IL, USA

   Matthew T. Leslie & Maeve Marsh

9. North Carolina Department of Health and Human Services, Raleigh, NC, USA

   Zin Lyons & Erin Ricketts

10. South Dakota Department of Health, Pierre, SD, USA

    Hayden D. Hedman & Joshua L. Clayton

11. Centers for Disease Control and Prevention, Atlanta, CA, USA

    J. Bradford Bertumen, Hayden D. Hedman, Umesh Parashar, M. Steven Oberste, Jacqueline E. Tate, Julia M. Baker, David Sugerman, Caelin Potts, Xiaoyan Lu, Preeti Chhabra, Olivia Almendares, Neha Balachandran, Jordan E. Cates, Brandi Freeman, Anita Kambhampati, Rachel Marine, Everardo Vega, Mary E. Wikswo, Erin R. McKeever, Jan Vinjé & Hannah L. Kirking

12. Association for Public Health Laboratories, Silver Spring, MD, USA

    Maureen Sullivan & Kelly Wroblewski

13. Alabama Department of Public Health, Montgomery, AL, USA

    L. Amanda Ingram

14. University of Alabama at Birmingham, Birmingham, AL, USA

    David Kelly, Henry Shiau, William Britt & Luz Helena Gutierrez Sanchez

15. Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Caroline Ciric & Christina A. Rostad

16. Department of Biomedical Science, University at Albany, SUNY, Albany, NY, USA

    Kirsten St. George

17. Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA

    Charles Y. Chiu

18. Chan-Zuckerberg Biohub, San Francisco, CA, USA

    Charles Y. Chiu

19. Baylor College of Medicine, Houston, TX, USA

    A. Julie & Leila C. Sahni

20. Seattle Children’s Research Institute, Seattle, WA, USA

    Janet A. Englund & Eileen J. Klein

21. Children’s Hospital Medical Center, Cincinnati, OH, USA

    Mary A. Staat

Authors

1. Venice Servellita
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2. Alicia Sotomayor Gonzalez
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3. Daryl M. Lamson
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4. Abiodun Foresythe
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5. Hee Jae Huh
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6. Adam L. Bazinet
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7. Nicholas H. Bergman
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8. Robert L. Bull
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9. Karla Y. Garcia
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10. Jennifer S. Goodrich
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11. Sean P. Lovett
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12. Kisha Parker
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13. Diana Radune
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14. April Hatada
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15. Chao-Yang Pan
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16. Kyle Rizzo
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17. J. Bradford Bertumen
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18. Christina Morales
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19. Paul E. Oluniyi
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20. Jenny Nguyen
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21. Jessica Tan
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22. Doug Stryke
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23. Rayah Jaber
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24. Matthew T. Leslie
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25. Zin Lyons
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26. Hayden D. Hedman
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27. Umesh Parashar
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28. Maureen Sullivan
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29. Kelly Wroblewski
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30. M. Steven Oberste
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31. Jacqueline E. Tate
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32. Julia M. Baker
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33. David Sugerman
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34. Caelin Potts
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35. Xiaoyan Lu
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36. Preeti Chhabra
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37. L. Amanda Ingram
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38. Henry Shiau
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39. William Britt
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40. Luz Helena Gutierrez Sanchez
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41. Caroline Ciric
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42. Christina A. Rostad
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43. Jan Vinjé
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44. Hannah L. Kirking
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45. Debra A. Wadford
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46. R. Taylor Raborn
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47. Kirsten St. George
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48. Charles Y. Chiu
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Consortia

Pediatric Hepatitis of Unknown Etiology Working Group

• Olivia Almendares
• , Neha Balachandran
• , Jordan E. Cates
• , Brandi Freeman
• , Anita Kambhampati
• , Rachel Marine
• , Everardo Vega
• , Mary E. Wikswo
• , Erin R. McKeever
• , David Kelly
• , A. Julie
• , Leila C. Sahni
• , Janet A. Englund
• , Eileen J. Klein
• , Mary A. Staat
• , Maeve Marsh
• , Erin Ricketts
• , Joshua L. Clayton
• , Natalia Cano
• , Miriam Oseguera
•  & Robert Blattner

Corresponding author

Correspondence to Charles Y. Chiu.

Supplementary information

Reporting Summary

Peer Review File

Supplementary Table 1

Detailed demographic, clinical, laboratory, and genomic characteristics for individual cases and controls.

Supplementary Table 2

Statistical associations of detected viruses in cases compared to controls.

Supplementary Table 3

Frequency of single nucleotide variants in AAV2 genomes from cases.

Supplementary Table 4

Primer sequences for detection and virus whole-genome sequencing of HAdV-41 and AAV2.

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Servellita, V., Gonzalez, A.S., Lamson, D.M. et al. Adeno-associated virus type 2 in US children with acute severe hepatitis. Nature (2023). https://ift.tt/U5BA6iK

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• Received: 11 September 2022

• Accepted: 10 March 2023

• Published: 30 March 2023

• DOI: https://ift.tt/U5BA6iK

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