A group from the Royal Children’s Hospital in Melbourne, Australia has reported the development of epilepsy after HHV-6 posttransplant limbic encephalitis (PALE) among children receiving stem cell transplantation with cord blood (CBT).  The group questions whether preemptive treatment is sufficient to prevent the high rate of death, epilepsy and permanent neurological deficits associated with HHV-6 PALE, and suggests that HHV-6 antiviral prophylaxis must be considered in all CBT patients.

Of 84 children children who underwent CBT at their institution, 6 (7%) developed HHV-6 PALE , and three of these six developed symptomatic generalized epilepsy (SGE) after a silent period of 11-18 months.  SGE is a condition characterized by progressive, global cognitive impairment with generalized epilepsy, and represents the most severe endpoint of several epileptogenic processes within the brain.  Of the three remaining patients with HHV-6 PALE, one patient died after development of a severe movement disorder and dysautonomia, and the other two two are under continued observation.

Although oligoclonal bands were only found in the CSF of one patient at the time of seizure, the authors also indicate the possibility of ongoing chronic viral replication below the level of threshold of detection in the CSF that may also be contributing to SGE.

Although the mechanism for this pathological condition has not been fully described, the group urges transplant specialists to implement precautionary measures to decrease the risk of developing SGE as a result of HHV-6 PALE:

“Nevertheless, regardless of the underlying mechanism, the potentially devastating and treatment-resistant consequences of HHV6 PALE in children warrant consideration of universal antiviral prophylaxis in recipients of CBT and prolonged immunomodulating or AED therapy during the postacute phase of PALE.”

For more information on the dangers of HHV-6 reactivation in transplantation, and on the role of HHV-6 in epilepsy, visit the following HHV-6 Foundation webpages:

HHV-6 & Transplant Complications

HHV-6 & Epilepsy

Written in a question/answer format, the group hopes that this article will help spread the word about ciHHV-6, a condition that affects nearly 1% of the worldwide population. The group advises physicians to use whole blood PCR tests to identify these patients and not to rely on serum or plasma tests to diagnose the condition. They suggest that any patient with greater than 500,000 DNA copies per ml in whole blood probably has HHV-6. Rarely, a patient with graft versus host disease or drug induced hypersensitivity syndrome will have a viral load above 500,000 copies, but this is transient and the viral load diminishes quickly. In an individual with ciHHV-6, the viral load will consistently be over 500,000 copies per ml in whole blood.

If you’d like to learn more about chromosomally integrated HHV-6, please visit our web page on ciHHV-6, or download the article at the link above.

112 (48%) experienced early reactivation of HHV-6.  Myeloablative conditioning and the use of cord blood as a stem cell source were identified as significant risk factors for HHV-6 reactivation.

Furthermore, antiviral therapy had a beneficial effect and was recommended by the authors.  A total of 44 symptomatic patients received antiviral therapy, and a treatment response was observed in 34 of 38 evaluable patients (89%). Of these, 14 patients achieved a negative HHV-6 result and 20 experienced significantly decreased HHV-6 load in response to antiviral therapy. The duration of HHV-6 reactivation was shorter in patients who received antiviral treatment compared with those who were not treated.

The group concludes that “careful monitoring of HHV-6 viral load is important” in patients undergoing allo-SCT, as early detection of HHV-6 and related clinical symptoms can be suggestive of acute GVHD.  Furthermore, they suggest that proper antiviral treatment for this complication should become a focus of future hematological research.  They recommend that all patients undergoing allo-SCT be monitored for HHV-6, particularly patients who are receiving cord blood as a stem cell source and who are experiencing symptoms related to HHV-6 reactivation post-transplantation, and antiviral treatment with foscarnet and/or ganciclovir be strongly considered for patients suspected of early HHV-6 reactivation.

For more information on the dangers of HHV-6 reactivation in transplantation, visit our webpage on HHV-6 & Transplant Complications.

However, although the detection of HHV-6 DNA in liver tissue biopsies was associated with decreased graft survival, other methods of HHV-6 detection were less reliable in predicting poor outcome.  For instance, the detection of HHV-6 IgM antibodies was not significantly correlated with any clinical outcome.  Furthermore, although the detection of HHV-6 DNA in blood samples was associated with significantly shorter survival in Kaplan Meier Analysis, it was not found to be significantly associated with decreased graft survival. These findings support the findings of other groups as well, and suggest that because HHV-6 is such a low copy number virus and can “smolder” actively in the tissues, blood testing may be misleading; the most useful tool for the proper detection and diagnosis of HHV-6 infection continues to be the evaluation of tissue biopsy.

In their study, samples from 173 liver transplant patients who presented with an episode of graft hepatitis—a liver complication which features the increase of liver enzymes, among other things—were retrospectively analyzed for the presence of potential etiological agents associated with reduced graft survival, defined as the time between initial transplantation and re-transplantation and/or death.  Samples such as tissue biopsy, serum, and whole blood—when available—from each patient were evaluated for the presence of EBV, CMV (both known to cause complications among liver transplant patients) and HHV-6.

HHV-6 was detected in 58% of liver biopsies, and high intrahepatic HHV-6 DNA levels (defined as the 75^th percentile; >11.27 copies/1000 cells) were significantly associated with decreased graft survival following diagnosis of graft hepatitis. Low levels of intrahepatic HHV-6 DNA, which indicate latent viral infection, were not associated with decreased graft survival. Furthermore, although elevated viral loads of both CMV and EBV were observed in some tissues, these values did not correlate with decreased graft survival.

This important publication suggests that HHV-6 may be a significant contributor to liver dysfunction, particularly in the liver transplant population, and merits further elucidation.  It also calls attention to the more broadly controversial issue of proper testing for HHV-6 infection, suggesting yet again that tissue biopsy may be the only way to identify a subset of patients who may benefit from anti-HHV-6 therapy.

Please visit our webpage on HHV-6 & Liver Disease for more information and resources regarding this disease association.

The authors emphasize the importance of endomyocardial biopsy and molecular analysis on frozen tissue—as opposed to fixed tissues—as HHV-6 was not detected in either serum or in paraffin fixed tissues of this patient, who died of an HHV-6 infection. The antibody titers for HHV-6 were not elevated. Endomyocardial biopsies are not performed for most myocarditis cases in the United States, although they are done routinely in many European countries.

HHV-6 infection has been reported to cause cardiac complications in both the immunocompromised and the immunocompetent, including myocarditis (Mahrholdt 2006) dilated cardiomyopathy (Comar 2009) and “idiopathic” left ventricle dysfunction (Kühl 2005). Despite a recent increase in publications that report HHV-6 myocarditis in immunocompromised patients, however, the virus’s role in the pathology of acute chronic myocarditis remains poorly defined.

Uwe Kühl, who leads a large cardiology practice at Charite-University in Berlin, treats HHV-6 positive myocarditis with valganciclovir and has achieved considerable success. His associate Dirk Lassner reported on these results at the 2011 International Conference on HHV-6 & 7. View video.

Click here to learn more about HHV-6 and Heart Disease.

Interferon beta (IFN-beta) is a common treatment in MS. Although the conventional wisdom is that the mechanism of action is “unkown”,  interferon is a natural antiviral that is often used for treatment of hepatitis  and enteroviruses. Interferon naturally inhibits viral replication, and in fact interferon was originally tested in MS patients because of its antiviral propertites.

The authors suggest that the exacerbations in MS could be explained by an immune reaction to the active replication, and that HHV-6 could be involved in MS through several mechanisms including a) increased death of HHV-6 infected neurons, astrocytes and oligodendrocytes, b) viral interference with the phosphorylation of myelin basic protein or c) increasing the glutamate level in the spinal fluid. HHV-6 is able to induce inflammation and demyelination. It has also been suggested that HHV-6 can interfere with the remyelination process.

The authors suggest further trials with other potential antivirals.

http://www.ncbi.nlm.nih.gov/pubmed/21518144

Jacobson’s team found that HHV-6A can infect the olfactory ensheathing cells that connect the nasal passages to the brain, giving the virus a direct pathway to the brain. See Science News article on this subject here. The finding has potentially enormous implications because it suggests that not one but several neurological conditions associated with loss of smell could be caused by virus.

Olfaction losses are found in the early stages of MS, Alzheimer’s, Parkinson’s schizophrenia and depression. (See Strous 2006 for a review.) Loss of smell is one of the first abnormalities and pathological abnormalities in the olfactory bulb are noticed early in the disease in Parkinson’s Disease. Importantly, the side with the worst loss of smell is opposite to the side with the worst movement disorder. (Zucco 2001)

Varicella virus and HSV-1 can also be found in the olfactory bulbs and an earlier study showed that HSV-1 infection via the nose led to virus latency in the amygdala and hippocampus in mice. (Becker 1995) Could these viruses cause quiet brain disease, smoldering in the brain tissue with no evidence in the blood? It is certainly an important question to study. Evidence has accumulated in recent years that strongly suggests that HSV-1 may play a major role in Alzheimer’s disease (Itzhaki 2008).

HHV-6A tie to MS

A group in Spain led by Roberto Alavarez-Lafuente has published several studies demonstrating that HHV-6A can be found in the serum and spinal fluid in a subset of relapsing remitting MS patients during active flares, but not during remission. Furthermore, he has found that HHV-6A reactivation in a subset of MS patients is strongly associated with two specific polymorphisms – IRF5 (which causes a reduction in interferon production) and MHC2TA (which affects MHC class II genes). The Spanish group has found no evidence of HHV-6B. Could this be because the olfactory ensheathing cells selectively allow HHV-6A but not HHV-6B access to the brain?

HHV-6A and oligodendrocyte precursor cells, astrocytes.

Of interest, David Mock’s group at University of Rochester reported in 2004 that HHV-6A establishes an abortive infection in oligodedrocyte precursors. This is significant because the abortive infection was associated with a profound reduction in the number of mature oligodendrocytes which are essential for the repair process. In fact, transplanted oligodendrocyte progenitor cells have recently been shown to remyelinate and restore spinal cord injury in mice.  The olfactory ensheathing cells also play a role in the repair process as they have significant neuro-regenerative properties as well. Both Jacobson and Yoshikawa in Japan have previously published that HHV-6A but not HHV-6B can infect astrocytes (u251 cells), important glial cells involved in axonal regeneration.

Virus and demyelination

Recently, researchers at the Oregon National Primate Research Center isolated a herpesvirus that they say has caused symptoms identical to MS in a small percentage of macaque monkeys every year. This suggests that HHV-6A – and perhaps other herpesvirus such as EBV and VZV may be involved in the pathogenesis of MS, in different subsets of MS.

This finding came as no surprise to HHV-6 investigators who have attended the HHV-6 Foundation conferences. In March 2011, Jacobson’s NINDS group demonstrated that HHV-6A intranasal inoculation in marmoset monkeys caused neurological disease very similar to MS. Of note, these monkeys showed no evidence of the viral DNA in the serum. (Download abstract.) Claude Genain presented similar evidence of HHV-6A induced neurological disease in marmosets at the 2008 conference (Download abstract), but was unable to find funding to expand his studies.  A group led by Brenda Horvat in France has also found that HHV-6A can cause brain lesions in CD46 transgenic mice. (Download abstract.)

Steve Jacobson, PhD and his team at the National Institute of Neurological Disorders and Stroke have published a new study that suggests HHV-6A can cause neurological disease by transmission through the nose. It is well known that loss of smell is a common prelude to many neurological diseases, but the reasons have never been understood.

Jacobson’s team found that HHV-6A can infect the olfactory ensheathing cells that connect the nasal passages to the brain, giving the virus a direct pathway to the brain. See Science News article on this subject here. The finding has potentially enormous implications because it suggests that not one but several neurological conditions associated with loss of smell could be caused by virus.

Olfaction losses are found in the early stages of MS, Alzheimer’s, Parkinson’s schizophrenia and depression. (See Strous 2006 for a review.) Loss of smell is one of the first abnormalities and pathological abnormalities in the olfactory bulb are noticed early in the disease in Parkinson’s Disease. Importantly, the side with the worst loss of smell is opposite to the side with the worst movement disorder. (Zucco 2001)

 Varicella virus and HSV-1 can also be found in the olfactory bulbs and an earlier study showed that HSV-1 infection via the nose led to virus latency in the amygdala and hippocampus in mice. (Becker 1995) Could these viruses cause quiet brain disease, smoldering in the brain tissue with no evidence in the blood? It is certainly an important question to study. Evidence has accumulated in recent years that strongly suggests that HSV-1 may play a major role in Alzheimer’s disease (Itzhaki 2008).

HHV-6A tie to MS

A group in Spain led by Roberto Alavarez-Lafuente has published several studies demonstrating that HHV-6A can be found in the serum and spinal fluid in a subset of relapsing remitting MS patients during active flares, but not during remission. Furthermore, he has found that HHV-6A reactivation in a subset of MS patients is strongly associated with two specific polymorphisms – IRF5 (which causes a reduction in interferon production) and MHC2TA (which affects MHC class II genes). The Spanish group has found no evidence of HHV-6B. Could this be because the olfactory ensheathing cells selectively allow HHV-6A but not HHV-6B access to the brain?

HHV-6A and oligodendrocyte precursor cells, astrocytes.

Of interest, David Mock’s group at University of Rochester reported in 2004 that HHV-6A establishes an abortive infection in oligodedrocyte precursors. This is significant because the abortive infection was associated with a profound reduction in the number of mature oligodendrocytes which are essential for the repair process. In fact, transplanted oligodendrocyte progenitor cells have recently been shown to remyelinate and restore spinal cord injury in mice.  The olfactory ensheathing cells also play a role in the repair process as they have significant neuro-regenerative properties as well. Both Jacobson and Yoshikawa in Japan have previously published that HHV-6A but not HHV-6B can infect astrocytes (u251 cells), important glial cells involved in axonal regeneration.

Virus and demyelination

Recently, researchers at the Oregon National Primate Research Center isolated a herpesvirus that they say has caused symptoms identical to MS in a small percentage of macaque monkeys every year. This suggests that HHV-6A – and perhaps other herpesvirus such as EBV and VZV may be involved in the pathogenesis of MS, in different subsets of MS.

This finding came as no surprise to HHV-6 investigators who have attended the HHV-6 Foundation conferences. In March 2011, Jacobson’s NINDS group demonstrated that HHV-6A intranasal inoculation in marmoset monkeys caused neurological disease very similar to MS. Of note, these monkeys showed no evidence of the viral DNA in the serum. (Download abstract) Claude Genain presented similar evidence of HHV-6A induced neurological disease in marmosets at the 2008 conference (Download abstract), but was unable to find funding to expand his studies.  A group led by Brenda Horvat in France has also found that HHV-6A can cause brain lesions in CD46 transgenic mice. (Download abstract)

A new study  from the Mayo Clinic, lead by Infectious Disease and Transplant specialist Dr. Raymund Razonable, looked at 548 cases of liver transplantation in an attempt to determine the clinical significance of CIHHV-6 among transplant patients.  While 1.3% of transplant patients were found to have CIHHV-6—a number consistent with the established prevalence of CIHHV-6 in the general population—the group found a higher rate of bacterial infection and allograft rejection in CIHHV-6 patients as compared to transplant recipients without the condition.   Their data suggest that patients with CIHHV-6 may be at an increased risk of complications following transplantation.

http://www.ncbi.nlm.nih.gov/pubmed/21629177

Click here to learn more about HHV-6 and Transplantation.

By examining 48 lymph node biopsies previously found positive for HHV-6B DNA, Lacroix et al demonstrated the presence of HHV-6B in the Reed Sternberg (RS) cells of 39.5% of the nodular sclerosis subset of HL, and even more surprising, they found that the HHV-6B specific protein DR7B was detected in 73.7% of these tissues.  Interestingly, this subset of HL tissue was EBV-negative.  By showing that HHV-6B transactivates NFkB and increases Id2 expression through the expression of DR7B, HHV-6 has now been implicated as an oncogenic agent in the nodular sclerosis subset of Hodgkin’s Lymphoma.  Also, detection of DR7B in the RS cells of EBV-negative HL patients may be considered as a surrogate marker for the identification of patients with a high probability of remission. (Lacroix 2010).

The evidence for HHV-6A seems strongest of all the viruses implicated, although these viruses potentiate each other and co-infections and interaction with endogenous retroviruses appear to play a role as well. Over the past five years, European researchers have shown that HHV-6A can be isolated from the serum and CSF in a subset of MS patients during relapse, and have linked HHV-6A reactivation to two genes associated with an increased risk for MS: IRF5 and MHC2TA rs4774C.

Steve Jacobson at NINDS has shown that there is an increased lymphoproliferative response to HHV-6 and that there are HHV-6 and EBV specific oligoclonal bands in MS patients. Finally, the Spanish investigators also demonstrated that the effectiveness of interferon beta 1b treatment in MS patients correlates with HHV-6 DNA levels, suggesting that it is the antiviral action of the interferon beta treatment that causes the therapeutic effect. Jacobson’s group presented evidence at the last HHV-6 conference last winter that HHV-6A can cause MS-like neurological disease in monkeys (unpublished), and a group from France demonstrated that HHV-6A can cause mice to develop lesions in the brain.

Where is the MS community and why aren’t patients demanding clinical trials with antivirals? Clinicians at NYU tried valacyclovir (Valtrex) in 2005, but this was the wrong drug. Valtrex (which converts to acyclovir) is not effective for HHV-6. The rationale for a trial of valganciclovir (Valcyte) is compelling. It crosses the blood brain barrier, has a relatively good safety profile, and is effective against HHV-6A. FDA approved for CMV retinitis, Valcyte is an oral drug that can be used safely as long as patients are monitored for bone marrow suppression. It has been used routinely as prophylaxis for herpesvirus reactivation in the transplant community for over ten years, with minimal adverse side effects.

The HHV-6A may only be a bystander, and it may be that abortive infection (not actual replication) is what is important in triggering MS. That doesn’t mean an HHV-6 and EBV specific antivirals shouldn’t be given a try – especially in those with signs of viral activity (elevated IgG titers or virus specific oligoclonal bands). It is pretty clear now that interferon works for MS because of the antiviral effect, but it is a relatively weak antiviral compared to the others used for viral reactivation in transplant patients.  What are neurologists waiting for?