Catholic Hematopoietic Stem Cell Transplantation Center, The Catholic University of Korea, Seoul, Korea

Correspondence to: D-W Kim, St Mary's Hospital, Catholic Hematopoietic Stem Cell Transplantation Center, College of Medicine, The Catholic University of Korea, #62 Youido-Dong, Youngdeungpo-Gu, Seoul 150-713, Korea (South); Fax: 82-2-785-1340

Leukemia (2002) 16, 958-959. DOI: 10.1038/sj/leu/2402403

TO THE EDITOR

Human herpesvirus 6 (HHV-6) is an increasingly recognized pathogen in hematopoietic stem cell transplantation (HSCT) recipients¹ and has recently been reported to cause encephalitis. To date, 13 cases of HHV-6 encephalitis after HSCT have been reported.^2,3,4 HHV-6 has been found to have greater susceptibility to ganciclovir and foscarnet. Foscarnet, however, is preferred because of a higher concentration in the cerebrospinal fluid (CSF) and only two cases of encephalitis were treated with just ganciclovir in previous reports.²

We experienced two cases of HHV-6 encephalitis after allogeneic HSCT and their characteristics are summarized in Table 1. One patient (case 1) began to show agitation on day +21, with signal abnormalities in radiologic study (Figure 1a), and a cellular hematuria developed over the following days. The other patient (case 2), 1 month after transplant, presented with fever, generalized skin rash and disorientation. His mental status finally decreased to a drowsy state on day +51. The possibilities of drug toxicity and metabolic influences were ruled out in both cases. Treatment with i.v. ganciclovir (5 mg/kg every 12 h) commenced when the PCR for HHV-6 variant B from the CSF, which was tested elsewhere,⁵ was positive (Figure 1b). The DNA of HHV-6 variant A, HSV type 1 and 2, EBV, and CMV was not detected from the CSF. The patients' neurological symptoms were resolved with 3 weeks of ganciclovir therapy, and clinical improvements accompanied with a regression of the signal abnormalities on MRI (case 1) and conversion of PCR to negative result in the CSF and serum samples.

Further analyses were performed to reveal the cause of hematuria in case 1. PCR analysis for the HHV-6 variant B from the urine samples showed positive results. No bacterial, fungal or mycobacterial pathogens were detected in the urine samples. DNA PCR⁶ for BKV and JCV and immunofluorescence staining with anti-adenovirus antibody (mouse monoclonal antibody, Chemicon International, Temecula, CA, USA) from the urine was also negative. Interestingly, an improvement in CNS symptoms also accompanied with a gradual decrease and final disappearance of the hematuria and PCR negativity for HHV-6 in the urine samples.

As HHV-6 has been found in the renal tubular endothelial cells and kidney,⁷ these clinical data imply a role of HHV-6 in hematuria that develops after HSCT. This suggests that HHV-6 is associated with urinary tract damage, but it cannot be considered as conclusive evidence because sporadic PCR positivity for HHV-6 in the urine was found in 9% of patients after HSCT.⁸

In conclusion, these cases stress the emerging role of HHV-6 in encephalitis after HSCT and usefulness of ganciclovir therapy. A link between a HHV-6 infection and a hemorrhagic cystitis has never been described elsewhere and still remains uncertain. Further research should be undertaken.

Acknowledgements

This work was supported by Korea Research Foundation Grant (KRF-1999-005-F00026).

1 Singh N, Carrigan D. Human herpes virus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996; 124: 1065-1071. MEDLINE

2 Singh N, Paterson DL. Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus. Transplantion 2000; 69: 2474-2479.

3 Bethge W, Beck R, Jahn G, Mundinger P, Kanz L, Einsele H. Successful treatment of human herpesvirus- 6 encephalitis after bone marrow transplantion. Bone Marrow Transplant 1994; 24: 1245-1248.

4 Tsujimura H, Iseki T, Date Y, Watanabe J, Kumagai K, Kikuno K, Yonemitsu H, Saisho H. Human herpesirus-6 encephalitis after bone marrow transplantation: magnetic resonance imaging could identify the involved sites of encephalitis. Eur J Haematol 1998; 61: 284-285. MEDLINE

5 Jarrett RF, Clark DA, Josephs SF, Onions DE. Detection of human herpesvirus-6 DNA in peripheral blood and saliva. J Med Virol 1990; 32: 73-76. MEDLINE

6 Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R. Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med 1986; 315: 230-234. MEDLINE

7 Asano Y, Yoshikawa T, Suga S, Yazaki T, Hirabayashi S, Ono Y, Tsuzuki K, Oshima S. Human herpesvirus 6 harboring in kidney. Lancet 1989; 2: 1391. MEDLINE

8 Wilborn F, Brinkmann V, Schmidt CA, Neipel F, Gelderblom H, Siegert W. Herpesvirus type 6 in patients undergoing bone marrow transplantation: serologic features and detection by polymerase chain reaction. Blood 1994; 83: 3052-3058. MEDLINE

Figure 1 Patient 1, MRI of the brain at the time of diagnosis (a) showed high signal intensities in the subcortical white matter around the right posterior frontal operacular region and the right temporal lobe. Analysis of the multiplex PCR products of patients by agarose gel electrophoresis after staining with ethidium bromide (b). Lane M, size marker (100 bp ladder). HHV-6-variant B DNA detected in the CSF at the time of diagnosis (1) was negative 3 weeks after ganciclovir therapy (2) as is the same in the urine (3 and 4). Lanes 5, 6 and 7, positive control for EBV (5), CMV (6), HHV-6B (7).

Table 1 Characteristics of the two patients