Accepted: 6 May 2018 DOI: 10.1111/petr.13239
ORIGINAL ARTICLE
Clinical course of human herpesvirus 6 infection in pediatric living donor liver transplantation Toshihiro Yasui1
| Tatsuya Suzuki1 | Tetsushi Yoshikawa2 | Hiroshi Yatsuya3 |
Yoshiki Kawamura2 | Hiroki Miura2 | Fujio Hara1 | Shunsuke Watanabe1 | Naoko Uga1 | Atsuki Naoe1 1 Department of Pediatric Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan 2
Abstract Differentiation between active and latent viral infection is critical for analysis of
Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
HHV-6-associated disease. HHV-6 infection has been associated with several clinical
3
clear. This retrospective cohort study included 33 pediatric patients who received
Department of Public Health, Fujita Health University School of Medicine, Toyoake, Aichi, Japan Correspondence Toshihiro Yasui, Department of Pediatric Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. Email:
[email protected]
manifestations; however, the precise role of HHV-6 in pediatric LDLT remains unLDLT. All of the recipients were monitored for HHV-6 infection using viral isolation and real-time PCR. HHV-6 infection was observed in 14 of 33 (42.4%) recipients, and HHV-6B infection occurred within 2 weeks after LDLT in 10 of 14 (71.4%) recipients. HHV-6 was isolated from 10 of 33 (30.3%) recipients. Multivariate analysis showed that independent predictors of HHV-6B infection were age (OR 0.975; 95% CI 0.943- 0.999; P = .041), PELD (OR 1.091; P = .038), and biliary atresia (OR 16.48; P = .035). The occurrence of unexplained fever was significantly higher in recipients with HHV-6B infection (11/14) compared with uninfected recipients (6/19) (P = .013). Additionally, ALT levels at 8 and 9 weeks after transplantation were significantly higher in the recipients with HHV-6B infection. Younger age, high MELD/PELD score, and biliary atresia as an underlying disease were identified as risk factors for viral infection. KEYWORDS
human herpesvirus, LDLT, pediatric liver transplantation, viral infection
1 | I NTRO D U C TI O N
infection with HHV-6B, which presents as exanthema subitum, occurs mainly in infants and young children and results in establishment of latent infection in mononuclear cells, the salivary gland, and glial cells.2-5
HHV-6B is a member of the β-herpesvirus subfamily. It was first dis-
In the general population, most children and adults are HHV-6 sero-
covered in the peripheral blood of patients with lymphoproliferative
positive.5 Although the clinical course of primary HHV-6B infection is
disorders and acquired immune deficiency syndrome in 1986.1 Primary
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BA, biliary atresia; CMV, cytomegalovirus; CNS, central nervous system; CsA, cyclosporine A; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; FK, tacrolimus; HHV-6B, human herpesvirus 6B; HHV-6, human herpesvirus 6; LDLT, living donor liver transplantation; MELD, model for end-stage liver disease; MMF, mycophenolate mofetil; mPSL, methylprednisolone; N.A., not applicable; PCR, polymerase chain reaction; PELD, pediatric end-stage liver disease; POD, postoperative day; PSL, prednisolone.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2018 The Authors. Pediatric Transplantation Published by Wiley Periodicals, Inc Pediatric Transplantation. 2018;e13239. https://doi.org/10.1111/petr.13239
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usually benign and self-limited, several severe complications such as encephalitis
6-8
9
and myocarditis have been reported.
cells, such as characteristics of pleomorphic, balloon-like large cells. The presence of HHV-6B was confirmed by immunofluorescence
HHV-6B can reactivate in immunocompromised patients, such as
staining of the cocultures with a specific HHV-6B monoclonal anti-
hematopoietic stem cell transplant and solid organ transplant recipients,
body (OHV-3; provided by T. Okuno, Department of Microbiology,
resulting in recurrent infection.10-12 HHV-6B infection has been associ-
Hyogo College of Medicine, Hyogo, Japan). Pretransplant HHV-6
ated with several clinical manifestations including fever, bone marrow
Immunoglobulin G antibody titers were measured by indirect-
suppression, hepatitis, acute rejection, and encephalitis in liver trans-
immunofluorescence assay as previously described.5
12,13
plant recipients.
However, there are conflicting reports regarding the
precise impact of HHV-6B infection on the clinical course of liver transplant recipients,14-17 particularly in pediatric liver transplant recipients.
2.3 | Monitoring of HHV-6B, CMV, and EBV DNA
The purpose of this study was to elucidate the risk factors for,
Viral DNA was extracted from serially collected peripheral blood mon-
clinical features of as well as the impact on the post- transplant
onuclear cells using the QIAamp Blood Kit (QIAGEN, Chatsworth, CA,
course of HHV-6B infection in pediatric LDLT recipients. Given that
USA). After extraction, the DNA was eluted in 100 μL of TE buffer and
HHV-6B infection was monitored using viral isolation and real-time
stored at −20°C. Real-time PCR for detection of the 3 human her-
PCR in all of the recipients at our institute, we were able to deter-
pesviruses, CMV,19 EBV,20 and HHV-6B, was carried out in 10 μL of
mine whether there was an association between active HHV-6B in-
extracted DNA. The details of the real-time PCR methods for meas-
fection and clinical features.
uring viral DNA loads were previously described.19-21 The detection limit of the assays was 10 copies/tube. If 1.0 × 104 copies/μg of
2 | M ATE R I A L S A N D M E TH O DS 2.1 | Study design
HHV-6 DNA was detected in peripheral blood mononuclear cells and/ or HHV-6 viremia was demonstrated, we defined it as HHV-6 infection. Additionally, primary infection and reactivation of the virus were distinguished based on pretransplant HHV-6 serostatus. If HHV-6-
This is a retrospective cohort study of 33 pediatric patients (
