- Grade III-IV GVHD
- Increased all-cause mortality
- Encephalitis
- Cognitive dysfunction & memory loss/Amnesia
- Myocarditis/peridcarditis
- Liver disease
- Atypical interstitial pneumonia
- Colitis
- Kidney disease
- Bone marrow suppression
- Opportunistic infection
- Rash & fever
- Delayed engraftment
- Hepatobiliary disorders
HHV-6 & Stem Cell Transplantation
HHV-6 encephalitis is a growing concern in the post-transplant setting, especially in cord blood transplants. Studies have shown around as many as 10% in the US and 12-16% in Japan develop HHV-6 encephalitis. Limbic encephalitis is common, resulting in intermittent confusion, poor coordination, flat affect and somnolence. Up to 80% of all HHV-6 encephalitis patients experience permanent neurological sequelae that do not allow them to return to society. Additional risk factors include steroid administration, alemtuzumab, thymobglobulin and unrelated donors.
Risk Factors for the Development of HHV-6 Encephalitis in Transplantation:
1. Cord blood transplant (Mori 2010)
2. Alemtuzumab (Vu 2007)
3. Thymoglobulin conditioning (Hill 2011)
4. Steroids (Ogata 2010)
5. Unrelated donors (Betts 2011)
6. Two or more HSCT (Mori 2010)
HHV-6 and Cognitive Dysfunction
HHV-6 reactivation is the most common cause of mental confusion among post-transplant patients (Zerr 2011). HHV-6-associated encephalitis also presents as retrograde and anterograde amnesia.
HHV-6 and GVHD
HHV-6 reactivation is also a cause of major complications after allogeneic hematopoietic stem cell transplantation (HSCT) and has been associated with acute graft-versus-host disease (aGVHD), allograft rejections, central nervous system dysfunction and increased mortality (de Pagter 2008). A recent survey of 235 allogeneic stem cell transplant patients indicated that post-transplant HHV-6 reactivation is strongly associated with delayed platelet engraftment, early posttransplantation mortality, and the development of acute GVHD (Dulery 2011).
| The Significance of HHV-6 Reactivation in Cord Blood Transplantation: Large Cohort Studies | ||
| Author & Year | Title | Results |
| Hill 2011 (ASH Mtg Abstract) | HHV-6 Associated post-transplantation acute limbic encephalitis following Cord Blood Stem Cell Transplantation: A Cohort Analysis | HHV-6 Post-Transplant Acute Limbic Encephalitis incidence rate was higher among UCBT patients (10/101, IR 1.2/1000 patient-days) compared with the rest of the allo-HSCT cohort (9/1243, IR 0.08/1000 patient-days, p<0.001). Other relevant characteristics associated with HHV6-PALE included acute graft-versus-host disease (GVHD) grade II-IV (p=0.05), adult mismatched donor (p=0.03) and conditioning with thymoglobulin (p=0.003). Of 68 UCBT patients who underwent plasma HHV6 PCR testing, 49 (72.1%) had positive results. |
| Pichereau 2011 | The Complex Relationship between HHV-6 and acute GVHD | Significant association between HHV-6 reactivation and the use of cord blood as the stem cell source (56.3% versus 22.3%; P < .0001) |
| Zerr 2011 | HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients | Cord Blood and unrelated transplantation significantly increased risk of HHV-6 reactivation |
| Sakai 2011 | Long-term outcome of HHV-6 encephalitis after allogeneic stem cell transplantation | Cord Blood transplantation was identified asthe only independent risk factor for the development of HHV-6 encephalitis |
| Betts 2011 | HHV-6 infection after HCT: is routine surveillance necessary? | More recipients of umbilical cord blood (UCB 69% vs unrelated donor [URD] 46% vs sibling donor [20%] grafts, P = 0.01) reactivated HHV-6. |
| Ishiyama 2011 | Preemptive therapy of HHV-6 encephalitis with PFA for high risk [atients after hematopoietic SCT | 12/15 UCBT recipients became positive for HHV-6 DNAemia, defined by greater than 100 copies/mL of HHV-6 DNA in plasma. The virus exceeded 500 copies/mL in seven patients, whereas none of the five HLA-haploidentical HSCT recipients became positive. |
| Chevallier 2010 | HHV-6 infection is a hallmark of CBT in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source. | Incidence of HHV6 infection was significantly higher in the CBT group (80% vs 42.5%; P<0.0001), with higher viral load. In multivariate analysis, the use of a CBT and a myeloablative conditioning regimen were found to increase the risk of HHV6 infection (odds ratio (OR)=5.4, P=0.02 and OR=3.5, P=0.04, respectively). |
| Mori 2010 | High Incidence of HHV6 encephalitis/myelitis following second unrelated CBT | 15.7% (8 of 51) UCBT recipients developed HHV-6 encephalitis compared to 2.8% (5 of 155) transplanted with stem cell or bone marrow transplants. This happened more freqently in those who received 2 or more HSCT. 7 showed symptoms of CIPS. |
| de Pagter 2008 | HHV-6 plasma DNA positivity after HSCT in children: an important risk factor for clinical outcome | Of all HSCT cases (58), 30/43 (69.8%) cases of bone marrow or peripheral blood stem cells grafts (all non-CBT) reactivated, and 9/15 (60.0%) cases of cord blood (CB) grafts reactivated. However, only 17/43 (39.5%) of non-CBT cases had severe (>1000 HHV-6 DNA copies/mL), while all 9/15 (60%) cases of CBT had severe reactivation. Severe reactivation (High DNA load) was found to be the only independent predictor of both GVHD and lower survival rate, mainly because of NRM. |
| Mata 2008 | HHV-6 associated limbic encephalitis in adult recipients of unrelated umbilical cord blood transplantation | Among 15 adult patients receiving UCBT, 2 developed acute neurological symptoms after transplantation; in both the cases, brain magnetic resonance imaging (MRI) and CSF PCR examination were suggestive of a HHV-6 limbic encephalitis. |
| Yamane 2007 | Risk Factors for developing HHV-6 reactivation after aHSCT and association with CNS disorders | 92.3% (12 of 13) unrelated CBT developed HHV-6 DNAemia |
| Tomonari 2005 | HHV-6B in adult patients after unrelated cord blood transplantation | HHV-6 reactivation was 70% at day 21, and associated with skin rash and acute GVHD |
| Sashihara 2002 | High incidence of HHV-6 infection with a high viral load in CBT recipients | Of the CBT recipients, 70% (7 of 10) had active HHV-6 infection after transplantation. A much higher percentage reactivate when those naïve to HHV-6 are removed |
Download a copy of The HHV-6 Foundation’s 2011 ASH Meeting Brochure, which has a collection of select abstracts and information on HHV-6′s role in hematological issues such as Hematopoietic Stem Cell Transplantation, Cognitive Dysfunction, GVHD, and more.
HHV-6 & Solid Organ Transplantation
In kidney transplant patients, HHV-6 has been associated with the development of chronic allograft nephropathy (Chapenko 2009) and GVHD (Caiola 2012). Consequences of HHV-6 reactivation in liver transplant patients include bone marrow suppression, central nervous system dysfunction, pneumonitis, hepatitis, increased severity of graft host disease, increased incidence of fungal infections and higher incidence of allograft rejection (Abdel Massih 2009). A recent publication indicates that high intrahepatic HHV-6 loads, but neither CMV nor EBV, are associated with decreased graft survival following diagnosis of graft hepatitis (Pischke 2012).
