Early HHV-6 replication is associated with morbidity non-related to CMV infection after kidney transplantation

Schroeder, Regina Barbosa; Michelon, Tatiana Ferreira; Garbin, Gabriela; Garcia, Valter; da Silveira, Janaina Gomes; Santos, Luciano; Neumann, Jorge; Keitel, Elizete

doi:10.1016/S1413-8670(12)70296-9

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Abstract

Human herpesvirus type 6-(HHV-6) has been associated with morbidity after liver transplantation.

Objective

The aim of this study was to determine the HHV-6 seroprevalence among donorrecipient pairs, analyze the incidence of early active infection, its clinical manifestation, interaction with CMV, and the related morbidity in the first year after kidney transplantation.

Methods

46 donor-recipient pairs had IgG evaluated by ELISA before transplantation: HHV-6-(Pambio – USA) and CMV-(Roche – USA). A frozen whole blood sample collected weekly (from the 1st to the 6th week) was retrospectively tested for HHV-6 viral load (VL) determination by real time quantitative PCR (qPCR, Nanogen – Italy). Patients were preemptively surveyed for CMV by pp65 antigenemia (Ag, APAAP, immunohistochemistry, Biotest – Germany) from the 4th to the 12th week after transplantation. Active infection was defined as qPCR-HHV6+ (viral-load/mL-VL) and Ag+ (+cells/100.000 granulocytes), for HHV-6 and CMV, respectively. DCMV was defined as simultaneous positive antigenemia and suggestive signs/symptoms. Concerning +qPCR-HHV6, associated factors, clinical manifestation, interaction with CMV and morbidity were searched.

Results

Pre-transplant HHV-6 seroprevalence was significantly higher among kidney recipients compared to their donors (82.6×54.8%; p=0.005 [3.9 (1.4–10.4)]). Active infection by this virus occurred in 26.1% (12/46), with no association with previous IgG (p=0.412). Median VL was 125 copies/mL (53–11.264), and the median Ag was 21 +cells (2–740). There was no association between HHV-6 and CMV activation after transplantation (p=0.441), neither concerning DCMV (p=0.596). Median highest Ag+ and days of ganciclovir treatment were similar between qPCR-HHV6 + or − (p=0.206 and p=0.124, respectively). qPCR-HHV6+ was associated with higher incidence of bacterial (p=0.009) and fungal (p = 0.001) infections, and higher number (p=0.001) of hospital admission and longer duration of hospitalization over the first 6 and 12 months post-transplantation (p=0.033 and p=0.001).

Conclusion

Latent HHV-6 infection is more common among recipients than donors before transplantation. Early active infection by this pathogen after transplantation does not increase DCMV incidence or severity during the first 3 months of follow-up. However, early HHV-6 replication is associated with other infections and hospitalizations in the first year.

Keywords:

Cytomegalovirus infections

Herpesvirus 6, human

DNA virus infections

Clinical diagnosis

Polymerase chain reaction

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References

[1.]

L. De Bolle, L. Naesens, E. De Clercq.

Update on human herpesvirus 6 biology, clinical features, and therapy.

Clin Microbiol Rev, 18 (2005), pp. 217-245

http://dx.doi.org/10.1128/CMR.18.1.217-245.2005 | Medline

[2.]

D.M. Zerr, A.S. Meier, S.S. Selke, et al.

A population-based study of primary human herpesvirus 6 infection.

N. Engl J. Med, 342 (2005), pp. 768

[3.]

R. Schroeder, T. Michelon, I. Fagundes, et al.

Cytomegalovirus disease latent and active infection rates during the first trimester after kidney transplantation.

Transplant Proc, 36 (2004), pp. 896-898

http://dx.doi.org/10.1016/j.transproceed.2004.03.085 | Medline

[4.]

N. Singh, D. Peterson.

Encephalitis caused by human herpesvirus-6 in transplant recipients.

Transplantation, 69 (2000), pp. 2474-2479

Medline

[5.]

D.C. Brennan.

Highlights From The Sixth Annual Ast Winter Symposium — Transplantation meets infection: microbes, rejection, atherosclerosis, and malignancy.

Medscape Transplantation, 3 (2002), pp. 1-14

[6.]

C. Tianssheng, D. Hudnall.

Anatomical mapping of human herpesvirus reservoirs of infection.

Mod Pathol, 19 (2006), pp. 726-737

http://dx.doi.org/10.1038/modpathol.3800584 | Medline

[7.]

P. Lusso.

Human herpesvirus 6 (HHV-6).

Antiviral Research, 31 (1996), pp. 1-21

Medline

[8.]

A.C. Schmidt, F. Wilborn, K. Weiss, et al.

A prospective study of human herpesvirus type 6 detected by polymerase chain reaction after liver transplantation.

Transplantation, 61 (1995), pp. 662

Medline

[9.]

N. Benito, A. Moreno, M. Pumarola, et al.

Virus del herpes humano tipo 6 y tipo 7 em receptores de transplante.

Enferm Infecc Microbiol Clin, 21 (2003), pp. 424-432

Medline

[10.]

J. Rogers, S. Rohal, D. Carrigan, et al.

Human herpesvirus-6 in liver transplant recipients.

Transplantation, 6 (2000), pp. 2566-2573

[11.]

V. Ratnamohan, J. Chapman, H. Howse.

Cytomegalovirus and human herpesvirus 6 both cause viral disease after renal transplantation.

Transplantation, 66 (1998), pp. 877-882

Medline

[12.]

J.A. Desjardin, E. Cho, S. Supran, et al.

Association of human herpesvirus 6 reactivation with severe cytomegalovirusassociated disease in orthotopic liver transplant recipients.

Clin Infect Dis, 33 (2001), pp. 1358-1362

http://dx.doi.org/10.1086/323336 | Medline

[13.]

R. Schroeder, T. Michelon, I. Fagundes, et al.

Antigenemia for cytomegalovirus in renal transplantation: choosing a cutoff for the diagnosis criteria in cytomegalovirus disease.

Transplant Proc, 37 (2005), pp. 2781-2783

http://dx.doi.org/10.1016/j.transproceed.2005.06.091 | Medline

[14.]

I. Lautenschlager, K. Linnavuori, K. Hockerstedt.

Human herpesvirus-6 antigenemia after liver transplantation.

Transplantation, 69 (2000), pp. 2561-2566

Medline

[15.]

S. Reddy, P. Manna.

Quantitative detection and differentiation of human herpesvirus 6 subtypes in bone marrow transplant patients by using a single real-time polymerase chain reaction assay.

Biol Blood Marrow Transplant, 11 (2005), pp. 530-541

http://dx.doi.org/10.1016/j.bbmt.2005.04.010 | Medline

[16.]

A.M. Visser, G.J. Van Doornum, J.J. Coernelissen, et al.

Severe amnesia due to HHV-6 Encephalitis after allogenic stem cell transplantation.

Eur Neurol, 54 (2005), pp. 233-234

http://dx.doi.org/10.1159/000090718 | Medline

[17.]

D. Boutolleau, C. Duros, P. Bonnafous, et al.

Identification of human herpesvirus 6 variants A and B by primer-specific realtime PCR may help to revisit their respective role in pathology.

J Clin Virol, 35 (2006), pp. 257-263

http://dx.doi.org/10.1016/j.jcv.2005.08.002 | Medline

[18.]

Al Komaroff, S. Jacobson.

Highlights from 5th international conference on HHV-6 and -7.

Herpes, 13 (2006), pp. 81-82

Medline

[19.]

D. Deborska-Materkowska, Z. Lewandowski, A. Sadowska, et al.

Fever, human herpesvirus 6 (HHV-6) seroconversion, and acute rejection episodes as a function of the initial seroprevalence for HHV-6 in renal transplant recipients.

Transplant Proc, 38 (2006), pp. 139-143

http://dx.doi.org/10.1016/j.transproceed.2005.11.093 | Medline

[20.]

I. Lautenschlager, M. Harma, K. Hockerstedt, et al.

Human herpesvirus-6 infection is associated with adhesion molecule induction and lymphocyte infiltration in liver allografts.

J Hepatol, 37 (2002), pp. 648-654

Medline

[21.]

J.C. Mendez, D.H. Dockrell, M.J. Espy, et al.

Human betaherpesvirus interactions in solid organ transplant recipients.

J Infect Dis, 183 (2001), pp. 179-184

http://dx.doi.org/10.1086/317929 | Medline

[22.]

M. Ohashi, K. Sugata, M. Ihira, et al.

Human herpesvirus 6 infection in adult living related liver transplant recipients.

Liver Transpl, 14 (2008), pp. 100-109

http://dx.doi.org/10.1002/lt.21304 | Medline

[23.]

A. Humar, A. Asberg, D. Kumar, et al.

An assessment of herpesvirus co-infection in patients with CMV disease: correlation with clinical and virologic outcomes.

Am J Transplant, 9 (2009), pp. 374-381

http://dx.doi.org/10.1111/j.1600-6143.2008.02501.x | Medline

[24.]

J.A. Desjardin, L. Gibbons, E. Cho, et al.

Human herpesvirus 6 reactivation is associated with cytomegalovirus and syndromes in kidney transplant recipients at risk for primary cytomegalovirus infection.

J Infect Dis, 178 (1998), pp. 1783

Medline

[25.]

A.S. Pacsa, S. Essa, A. Voevodin, et al.

Correlation between CMV genotypes, multiple infections with herpesviruses (HHV-6,7) and development of CMV disease in kidney recipients in Kiwait.

FEMS Immunol and Med Microbiol, 35 (2003), pp. 125-130

[26.]

S. Yang, R.E. Rothman.

PCR-based diagnostics for infectious diseases: uses, limitations, and future applications in acutecare settings.

Lancet Infect Dis, 4 (2004), pp. 337-348

http://dx.doi.org/10.1016/S1473-3099(04)01044-8 | Medline

[27.]