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Screening for chromosomally integrated human herpesvirus 6 status in solid-organ donors and recipients
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CASE ANECDOTES, COMMENTS AND OPINIONS Screening for chromosomally integrated human herpesvirus 6 status in solid-organ donors and recipients Bibhuti B. Das, MD,a and Flor M. Munoz, MDb From the aDepartment of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA; and the bDepartment of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
The article by Das et al suggested that a woman with chromosomally integrated human herpesvirus 6 (ciHHV-6) may have had her inherited virus activated by high-dose progesterone during pregnancy causing infectious virus to be transmitted transplacentally to her fetus, and thus causing a severe form of dilated cardiomyopathy at birth.1 Now that it has been documented that HHV-6 can reactivate from the ciHHV-6 stage,1,2 should patients who are ciHHV-6 positive be transplanted? At present, the biologic consequences of ciHHV-6 are an understudied research area, and the long-term proliferative potential of ciHHV-6þ solid organs remains to be defined. HHV-6 is unique among herpesviruses in its ability to integrate into the chromosome in the telomere, and the fact that this integrated virus can be passed through the germ-line in a Mendelian fashion. As ciHHV-6 can be present in approximately 1% of donors and 2% of patients, it can affect 3% of all transplants, with potentially serious consequences on the outcome of solid-organ transplantation.3,4 HHV-6 can cause encephalitis, myocarditis and hepatitis in immunocompromised patients.5 Transplant centers around the world routinely test both adult and pediatric hematopoietic stem cell transplant cases for HHV-6 serostatus. In an individual with ciHHV-6, the virus may or may not be active, but it is impossible to tell from the DNA viral load. ciHHV-6 status can be easily determined with a whole blood quantitative polymerase chain reaction (qPCR) DNA test because these individuals typically will have 4log 5.5 copies per milliliter or 1 copy per white blood cell. ciHHV6 status cannot be determined by a plasma PCR test, as the viral load is several logs lower in these assays. The failure rate of ciHHV-6þ donor organs has not been studied, but there is a strong common-sense argument for ciHHV-6 screening in solid-organ transplants, because: (a) we know that the inherited ciHHV-6 virus can activate under conditions of immunosuppression2-4; (b) patients with ciHHV-6, or patients who receive ciHHV-6 organs, may
require anti-viral prophylaxis or pre-emptive treatment; and (c) ciHHV-6 status can create confusion because physicians may misinterpret HHV-6 DNA from a ciHHV-6-affected patient as active infection and administer unnecessary antiviral medication. High-dose steroids can activate HHV-6 disproportionately compared with cytomegalovirus (CMV) and Epstein-Barr virus.6 Furthermore, HHV-6 reactivation in immunocompromised patients can increase the risk of CMV reactivation by 15-fold.7 Therefore, we propose that the ciHHV-6 status of the donors/recipients be determined before organ transplant using a single pre-transplant qPCR test on whole blood, and that patients with ciHHV-6 or ciHHV-6þ organs be carefully monitored for signs of active HHV-6 infection. Plasma PCR for HHV-6 is not very useful in determining viral reactivation in individuals with ciHHV-6 because there is a high background level of DNA from lysed cells. Therefore, physicians must use clinical judgment to determine whether HHV-6 is active. The only assay that can reveal whether the virus is replicating measures mRNA. This assay, currently performed only at a handful of research centers, could be used if it became more widely available.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Das BB, Rakheja D, Lacelle C, et al. Possible progesterone-induced gestational activation of chromosomally integrated human herpesvirus 6B and transplacental transmission of activated human herpesvirus 6B. J Heart Lung Transplant 2016;35:1373-6. 2. Endo A, Watanabe K, Ohye T, et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpes 6A in a patient with X-linked severe combined immunodeficiency. Clin Infect Dis 2014;59:545-8. 3. Flamand L. Pathogenesis from the reactivation of chromosomally integrated human herpesvirus type 6: facts rather than fiction. Clin Infect Dis 2014;59:549-51. 4. Pellet PE, Ablashi DV, Ambros PF, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol 2012;22:144-55. 5. Agut H, Bonnafous P, Gautheret-Dejean A. Update on infections with human herpes viruses 6A, 6B, and 7 [e-pub ahead of print]. Med Mal Inf http://dx.doi.org/10.1016/j.medmal.2016.09.004, accessed January 23, 2017. 6. Ishida T, Kano Y, Mizukawa Y, et al. The dynamics of herpes virus activations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome. Allergy 2014;69:798-805. 7. Crocchiolo R, Giordano L, Rimondo A, et al. Human herpesvirus 6 replication predicts cytomegalovirus reactivation after allogenic stem cell transplantation from haploidentical donor. J Clin Virol 2016;84:24-6.
1053-2498/$ - see front matter r 2017 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2017.01.004
CASE ANECDOTES, COMMENTS AND OPINIONS Screening for chromosomally integrated human herpesvirus 6 status in solid-organ donors and recipients Bibhuti B. Das, MD,a and Flor M. Munoz, MDb From the aDepartment of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA; and the bDepartment of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
The article by Das et al suggested that a woman with chromosomally integrated human herpesvirus 6 (ciHHV-6) may have had her inherited virus activated by high-dose progesterone during pregnancy causing infectious virus to be transmitted transplacentally to her fetus, and thus causing a severe form of dilated cardiomyopathy at birth.1 Now that it has been documented that HHV-6 can reactivate from the ciHHV-6 stage,1,2 should patients who are ciHHV-6 positive be transplanted? At present, the biologic consequences of ciHHV-6 are an understudied research area, and the long-term proliferative potential of ciHHV-6þ solid organs remains to be defined. HHV-6 is unique among herpesviruses in its ability to integrate into the chromosome in the telomere, and the fact that this integrated virus can be passed through the germ-line in a Mendelian fashion. As ciHHV-6 can be present in approximately 1% of donors and 2% of patients, it can affect 3% of all transplants, with potentially serious consequences on the outcome of solid-organ transplantation.3,4 HHV-6 can cause encephalitis, myocarditis and hepatitis in immunocompromised patients.5 Transplant centers around the world routinely test both adult and pediatric hematopoietic stem cell transplant cases for HHV-6 serostatus. In an individual with ciHHV-6, the virus may or may not be active, but it is impossible to tell from the DNA viral load. ciHHV-6 status can be easily determined with a whole blood quantitative polymerase chain reaction (qPCR) DNA test because these individuals typically will have 4log 5.5 copies per milliliter or 1 copy per white blood cell. ciHHV6 status cannot be determined by a plasma PCR test, as the viral load is several logs lower in these assays. The failure rate of ciHHV-6þ donor organs has not been studied, but there is a strong common-sense argument for ciHHV-6 screening in solid-organ transplants, because: (a) we know that the inherited ciHHV-6 virus can activate under conditions of immunosuppression2-4; (b) patients with ciHHV-6, or patients who receive ciHHV-6 organs, may
require anti-viral prophylaxis or pre-emptive treatment; and (c) ciHHV-6 status can create confusion because physicians may misinterpret HHV-6 DNA from a ciHHV-6-affected patient as active infection and administer unnecessary antiviral medication. High-dose steroids can activate HHV-6 disproportionately compared with cytomegalovirus (CMV) and Epstein-Barr virus.6 Furthermore, HHV-6 reactivation in immunocompromised patients can increase the risk of CMV reactivation by 15-fold.7 Therefore, we propose that the ciHHV-6 status of the donors/recipients be determined before organ transplant using a single pre-transplant qPCR test on whole blood, and that patients with ciHHV-6 or ciHHV-6þ organs be carefully monitored for signs of active HHV-6 infection. Plasma PCR for HHV-6 is not very useful in determining viral reactivation in individuals with ciHHV-6 because there is a high background level of DNA from lysed cells. Therefore, physicians must use clinical judgment to determine whether HHV-6 is active. The only assay that can reveal whether the virus is replicating measures mRNA. This assay, currently performed only at a handful of research centers, could be used if it became more widely available.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Das BB, Rakheja D, Lacelle C, et al. Possible progesterone-induced gestational activation of chromosomally integrated human herpesvirus 6B and transplacental transmission of activated human herpesvirus 6B. J Heart Lung Transplant 2016;35:1373-6. 2. Endo A, Watanabe K, Ohye T, et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpes 6A in a patient with X-linked severe combined immunodeficiency. Clin Infect Dis 2014;59:545-8. 3. Flamand L. Pathogenesis from the reactivation of chromosomally integrated human herpesvirus type 6: facts rather than fiction. Clin Infect Dis 2014;59:549-51. 4. Pellet PE, Ablashi DV, Ambros PF, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol 2012;22:144-55. 5. Agut H, Bonnafous P, Gautheret-Dejean A. Update on infections with human herpes viruses 6A, 6B, and 7 [e-pub ahead of print]. Med Mal Inf http://dx.doi.org/10.1016/j.medmal.2016.09.004, accessed January 23, 2017. 6. Ishida T, Kano Y, Mizukawa Y, et al. The dynamics of herpes virus activations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome. Allergy 2014;69:798-805. 7. Crocchiolo R, Giordano L, Rimondo A, et al. Human herpesvirus 6 replication predicts cytomegalovirus reactivation after allogenic stem cell transplantation from haploidentical donor. J Clin Virol 2016;84:24-6.
1053-2498/$ - see front matter r 2017 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2017.01.004