HHV-6 and Complications in Transplantation

Wisconsin Viral Research Group, Ltd.

Physician's Corner: Transplantation

HHV-6 in Transplantation

HHV-6 has received extensive study with respect to its pathogenic potential in bone marrow and solid organ transplant patients. Several review articles have recently appeared that summarize the basic findings in this area of research [1,2,3,4,5]. It is generally agreed that the vast majority of adult transplant recipients are seropositive for HHV-6 prior to transplant, that HHV-6 reactivates to an active infection at some point in approximately 50% of the patients and that the reactivations occur relatively early after transplant, i.e. during the first 2 to 4 weeks after transplant.

The clinical manifestations of HHV-6 infections in these patients are not subject to such a clear consensus. Interpretation of the clinical data is complicated by the facts that different types of transplant recipients vary widely with respect to their degree of immunosuppression, that transplantation protocols vary between different programs and institutions, and that different diagnostic procedures have been applied to patient samples in the various studies that have been reported.

In general, investigations using leukocyte PCR, tissue PCR or serology as the primary diagnostic methods have given inconsistent and contradictory results. For example, some investigators have concluded that the HHV-6 reactivations cause significant clinical disease [6] (bone marrow suppression and CNS disease), while other authors have failed to observe such disease associations [7]. Differences - in the various patient populations studied, in the details of the study protocols, and in the relative sensitivities of the PCR techniques used - probably account for these contradictory conclusions.

In contrast, studies in which the diagnostic methods used could only detect active HHV-6 infections have consistently identified disease associations with the infections. Isolation of HHV-6 in cell culture by classical procedures [8,9,10,11,12] and by our laboratory's rapid culture method [10] from samples of blood and bone marrow have strongly implicated HHV-6 as a cause of bone marrow suppression and CNS disease in both BMT and liver transplant patients. Immunohistochemical staining procedures have supported a role for HHV-6 in bone marrow suppression in BMT patients [13] and demonstrated the ability of the virus to cause fatal encephalitis in BMT patients [14; K Knox and D Carrigan, data not shown].

Several recent articles have appeared in which the clinical manifestations of HHV-6 in BMT and solid organ transplant patients were reviewed [1,2,3,4,5]. The strongest consensus among these authors is that HHV-6 infections cause fever, bone marrow suppression (both delayed engraftment and suppression of one or more bone marrow cell lineages) and CNS disease in both BMT and solid organ transplant patients.

As with cytomegalovirus infections [15], only a portion of immunocompromised patients with active HHV-6 infections will develop clinical disease in association with the infection. Approximately 33% of BMT patients who were positive for active HHV-6 infection in their blood showed rashes and other clinical manifestations [11,12]. HHV-6 infection of bone marrow accounted for 40% of cases of idiopathic bone marrow suppression in allogeneic BMT patients [9]. In a prospective study of autologous BMT patients, 44% of the patients were positive for HHV-6 infections by virus isolation from their blood and 50% of these patients showed significant bone marrow suppression concurrent with the virus isolation [K Knox, D. Carrigan et al., unpublished data].

In prospectively studied liver transplant patients, 50% (5/10) were positive for HHV-6 infection by virus isolation from blood within 5 weeks of transplant, and 60% (3/5) of these virus positive patients showed concurrent fever, 40% (2/5) showed associated thrombocytopenia, and 20% developed associated mental status changes (N Singh, personal communication). In a more extensive prospective study of liver transplant patients [16], HHV-6 reactivations accounted for 80% of the cases of idiopathic leukopenia and were the predominant cause of febrile illnesses after transplant. Thus, this data suggests that the incidence of HHV-6 associated disease ranges from approximately 30% to 60% in patients who are actively viremic, an incidence similar to that observed with CMV [15].

References

1.     Singh N and Carrigan DR. Human herpesvirus 6 in transplantation: An emerging pathogen. Ann Intern Med 1996; 124:1065-1071.

2.     Levy JA. Three new human herpesviruses (HHV6,7, and 8). Lancet 1997; 349:558-563.

3.     Carrigan DR and Knox KK, Pathogenic role of human herpesvirus six in transplantation. Current Opinion in Organ Transplantation 1999; Volume 4: in press.

4.     Kimberlin DW. Human herpesviruses 6 and 7: Identification of newly recognized viral pathogens and their association with human disease. Ped Infect Dis J 1998; 17:59-67.

5.     Braun DK, Pellett PE and Domingues G. Human herpesvirus six. Clin Microbiol Rev 1997; 10:521-567.

6.     Wang FZ, Dahl H, Linde A et al. Lymphotropic herpesviruses in allogeneic bone marrow transplantation. Blood 1996; 88:3615-3620.

7.     Wilborn F, Brinkmann V, Schmidt CA et al. Herpesvirus type 6 in patients undergoing bone marrow transplantation: serologic features and detection by polymerase chain reaction. Blood 1994; 83:3052-3058.

8.     Drobyski WR, Dunne WM, Burd EM et al. Human herpesvirus 6 (HHV-6) infection in allogeneic bone marrow transplant recipients: I. Evidence for a marrow suppressive role for HHV-6 in vivo. J Infect Dis 1993; 167:735-739.

9.     Carrigan DR and Knox KK. Human herpesvirus six (HHV-6) isolation from bone marrow: HHV-6 associated bone marrow suppression in bone marrow transplant patients. Blood 1994; 84:3307-3310.

10.     Singh N, Gayowski T and Carrigan DR. Human herpesvirus six (HHV-6) infection in liver transplant recipients: Documentation of pathogenicity. Transplantation 1997; 64, 674-678.

11.     Yoshikawa T, Suga S, Asano Y et al. Human herpesvirus 6 infection in bone marrow transplantation. Blood 1991; 78:1381-1384.

12.     Frenkel N, Katsafanas GC, Wwyatt LS et al. Bone marrow transplant recipients harbor the B variant of human herpesvirus 6. Bone marrow transplant 1994; 14: 839-843.

13.     Knox KK and Carrigan DR. Chronic marrow suppression in a bone marrow transplant patient associated with persistent HHV-6 marrow infection. Clin Infect Dis 1996; 22:174-175.

14.     Drobyski WR, Knox KK, Majewski D et al. Fatal encephalitis due to variant B human herpesvirus 6 infection in a bone marrow transplant recipient. N Engl J Med 1994; 330:1356-1360.

15.     Meyers JD, Ljungman P and Fisher LD. Cytomegalovirus excretion as a predictor of cytomegalovirus disease after transplantation: importance of cytomegalovirus viremia. J Infect Dis 1990; 162:373-380.

16. Singh N, Chang FY, Gayowski T et al. Fever in liver transplant recipients in the 1990's: changing spectrum of etiologies. Abstract J95. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. September, 1997.

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