Encephalitis caused by human herpesvirus‐6B in pancreas‐after‐kidney transplantation

Human herpesvirus‐6 (HHV‐6) is a common pathogen among children, classically presenting with fever and rash that resolves without specific therapy. HHV‐6 can be reactivated in the immunosuppressed patient. After bone marrow and solid organ transplantation, HHV‐6 has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, myelitis, hepatitis, pneumonitis, and bone marrow suppression. However, HHV‐6 encephalitis after pancreatic transplant has rarely been reported. Early diagnosis and treatment of HHV‐6 encephalitis may be important for affected patients. We report the case of a 53‐year‐old pancreas‐after‐kidney transplant recipient who initially presented with high fever and confusion 3 weeks after operation. We managed to save the patient's life and preserve the pancreas graft function. We also review previously reported cases of HHV‐6B encephalitis in solid organ transplant recipients.     

Chromosomally integrated human herpesvirus‐6 in transplant recipients

Human herpesvirus‐6 (HHV‐6) is unique among human herpesviruses because of its ability to integrate into chromosomes. This entity, termed chromosomally integrated HHV‐6 (CIHHV‐6), is often mistaken for active infection and treated unnecessarily. The clinical significance of CIHHV‐6 in transplant recipients is not defined. Herein, the clinical characteristics of 7 liver transplant patients with CIHHV‐6 from our recent study, together with 14 other published cases of CIHHV‐6 were reviewed. Of the 21 cases, CIHHV‐6B was reported most commonly among solid organ transplant recipients, while CIHHV‐6A was mostly seen in allogeneic hematopoietic stem cell recipients. None of the 21 patients developed clinical symptoms related to HHV‐6 after transplantation. However, antiviral therapy was administered to 5 asymptomatic patients mistaken to have HHV‐6 infection because of their very high HHV‐6 DNA levels, 3 who developed symptomatic cytomegalovirus disease, and 1 with graft‐versus‐host disease that was mistaken for HHV‐6 infection. In patients who received antiviral therapy, there was no apparent decline in HHV‐6 DNA load, although change in viral kinetics is difficult to discern in the setting of high baseline HHV‐6 DNA load. Clinicians should be aware of this entity of CIHHV‐6 so that antiviral therapy can be considered in the proper clinical context.     

Transmission of chromosomally integrated human herpesvirsus 6 (HHV‐6) variant A from a parent to children leading to misdiagnosis of active HHV‐6 infection

Abstract: Only a handful of cases of chromosomally integrated human herpesvirus 6 (CI‐HHV‐6) have been reported, suggesting that this phenomenon is rare. We here present a familial case of HHV‐6 variant A (HHV‐6A) transmission through a generation, which was identified in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). A 31‐year‐old man with myelodysplastic syndrome underwent allogeneic HSCT from a human leukocyte antigen‐identical sibling, and was found to be continuously yielding high copy numbers of HHV‐6A DNA in plasma evaluated by real‐time polymerase chain reaction (PCR). Antiviral therapy with ganciclovir or foscarnet failed to decrease the copy numbers. HHV‐6A DNA was detected in the patient's buccal mucosa and hair follicles, and was also detected in the plasma, whole blood, and buccal mucosa of the patient's father and 2 siblings, but not in his mother. The sequences of HHV‐6A DNA isolated from all family members were identical. Since monitoring of HHV‐6 by PCR has been widely introduced to the field of HSCT, transplant physicians should be aware of such an alternative form of HHV‐6 transmission, particularly when HHV‐6A is detected.     

Exanthem subitum (human herpesvirus‐6 reactivation) after autologous stem cell transplantation

We present the case of a 62‐year‐old man treated with high‐dose chemotherapy and consecutive autologous stem cell transplantation for mantle cell lymphoma, who developed high fever and a rash of the trunk and both axillae 10 days after stem cell transplantation.     

Ex vivo expansion of mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) are adult multipotent cells that can be isolated from several human tissues. MSCs represent a novel and attractive tool in strategies of cellular therapy. For in vivo use, MSCs have to be ex vivo expanded in order to reach the numbers suitable for their clinical application. Despite being efficacious, the use of fetal calf serum for MSC ex vivo expansion for clinical purposes raises concerns related to immunization and transmission of zoonoses; the standardization of expansion methods, possibly devoid of animal components, such as those based on platelet lysate, are discussed in this paper. Moreover, this review focuses on the search of novel markers for the prospective identification/isolation of MSCs and on the potential risks connected with ex vivo expansion of MSCs, in particular that of their malignant transformation. Available tests to study the genetic stability of ex vivo expanded MSCs are also analyzed.     

Antiviral prophylaxis may prevent human herpesvirus‐6 reactivation in bone marrow transplant recipients

Abstract: Human herpesvirus‐6 (HHV‐6) infects the majority of children under the age of 2 years causing roseola infantum. Following short self‐limited disease, the virus enters into a latency phase in peripheral blood lymphocytes (PBL). It has been previously reported that HHV‐6 reactivation from latency, in immunocompromised patients undergoing bone marrow transplantation (BMT), could result in febrile illness, pneumonitis, meningitis, and/or encephalitis. In our study, 14 BMT patients received two different antiviral prophylactic therapies: 8 patients received acyclovir, whereas 6 patients received ganciclovir. Clinical manifestations and virus recovery were monitored pre‐ and post‐BMT by polymerase chain reaction tests of cord blood cells cultured with the patients' PBL. No HHV‐6 recovery was shown in the 6 patients treated with ganciclovir, whereas 3 of the 8 acyclovir‐treated patients experienced virus reactivation 20–21 days post‐BMT. One of the 3 patients was asymptomatic but had late engraftment; the second patient had prolonged fever, skin rash, and hemorrhage; the third patient experienced prolonged fever, pneumonitis, marrow rejection, and fatal encephalitis. It is concluded that viral reactivation may be prevented by prophylactic treatment with ganciclovir. Our observation awaits further documentation in prospective randomized trials in high‐risk BMT recipients.     

Immune regulatory cells in umbilical cord blood: T regulatory cells and mesenchymal stromal cells

A major goal in haematopoietic cell transplantation (HCT) is to retain the lymphohaematopoietic potential of the cell transfer without its side effects. In addition to the physical injury caused by the conditioning regimen, donor T cells can react to alloantigens of the recipient and cause graft- versus -host disease (GVHD), which accounts for the largest share of morbidity and mortality after HCT. Immune modulator cells, such as regulatory T cells (Tregs) and mesenchymal stromal cells (MSCs) have shown promise in their ability to control GVHD and yet, in preclinical models, preserve the graft- versus -malignancy effect. Initially, MSCs and Tregs have been isolated from adult sources, such as bone marrow or peripheral blood, respectively. More recent studies have indicated that umbilical cord blood (UCB) is a rich source of both cell types. We will review the current data on UCB-derived Tregs and MSCs and their therapeutic implications.     

Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid‐refractory,grade III–IV acute graft‐versus‐host disease

Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.     

Bone marrow stromal mesenchymal cells induce down regulation of CD20 expression on B‐CLL: implications for rituximab resistance in CLL

Although the majority of B cells express surface CD20 in chronic lymphocytic leukaemia (B‐CLL), only ～50% of patients respond to treatment with rituximab. Decreased CD20 expression on these tumour B cells could be responsible for the lack of response observed in some patients treated with rituximab. Despite the potential critical role of CD20 in the biology of B cell malignancies, the mechanisms controlling its expression are poorly understood. At the bone marrow level, mesenchymal stromal cells (MSC) may regulate and support the survival of malignant cells, such as B‐CLL cells. In this study, we investigated whether MSC may regulate the CD20 expression on B‐CLL. For this purpose, B cells from CLL patients were isolated and co‐cultured on MSC. B‐CLL cells were collected from B‐CLL/MSC co‐cultures and examined for their expression of CD20. We demonstrate decreased CD20 expression in B‐CLL cells after 2 weeks of co‐culture with MSC, under contact and non‐contact conditions, which was associated with a decreased susceptibility to rituximab. Additionally, B cells co‐cultured with MSCs show an increase in CD59 expression. Our findings strongly suggest that the interaction between B‐CLL cells and MSC may play a major role in the resistance to rituximab‐induced apoptosis of B‐CLL cells.     

Hepatitis due to human herpesvirus 6B after hematopoietic cell transplantation and a review of the literature

Human herpesvirus 6B (HHV‐6B) is an opportunistic pathogen associated with a growing number of complications in immunocompromised patients. Multiple reports of HHV‐6B‐associated hepatitis following primary HHV‐6 infection and liver transplantation have appeared, but this has only been well documented in 1 patient after hematopoietic cell transplantation (HCT). This report describes a case of acute hepatitis likely caused by HHV‐6B in an HCT recipient who was successfully treated with ganciclovir. HHV‐6B DNA was demonstrated in plasma and hepatic tissue using quantitative polymerase chain reaction and immunohistochemical stains. Chromosomal integration was ruled out. We review the literature reporting HHV‐6B‐associated hepatitis, which may be an underappreciated cause of liver disease after HCT.     

Human herpesvirus‐6 as an inducer of porphyria cutanea tarda: implications from a case

T. Weber, S. Theurich, M. Christopeit, T. Klapperstueck, G. Behre. Human herpesvirus‐6 as an inducer of porphyria cutanea tarda: implications from a case.
Transpl Infect Dis 2010: 12: 432–436. All rights reserved Abstract: Here we describe a case that might deliver a link between sporadic porphyria cutanea tarda (PCT) and human‐herpesvirus‐6 (HHV6) hepatitis. Sporadic PCT is a rare disease of the heme synthesis pathway. The pathogenesis has not been fully determined but iron overload and viral infections – e.g., hepatitis C virus – are thought to play an important role. We present the case of a patient suffering from myelo‐monocytic leukemia. He developed symptomatic sporadic PCT concomitant with HHV6‐associated subclinical hepatitis after allogeneic stem cell transplantation (SCT). Although HHV6 often reactivates after SCT and HHV6‐induced hepatitis can occur in immunocompromised patients, it has not been described that HHV6 might trigger PCT. A contribution of HHV6 to the pathogenesis of sporadic PCT could have dramatic implications on our current therapeutic approach.