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Intensive care (ICU) patients with co-infections of HHV-6 and CMV are 7.5x more likely to die or have an extended stay in the hospital.
Japanese investigators published findings suggesting that HHV-6B plays a pathogenic role in epilepsy by enhancing gene expression that induces neuroinflammation and sclerosis in the temporal lobe. A pivotal study, led by Michael Boeckh at the Fred Hutchinson Cancer Research Center, has determined that occult infections contribute to 57% of all cases of “idiopathic” pneumonia syndrome (IPS), a condition previously assumed to be non-infectious. Delirium associated with HHV-6B reactivation in cord blood transplant patients: time for an antiviral prophylaxis trial? A prospective study authored by Joshua Hill and Danielle Zerr determined that higher than average HHV-6B DNA levels increased the odds of developing delirium after cord blood transplantation (CBT) by almost three fold. HHV-6 has been associated with various clinical complications, including roseola, chronic fatigue syndrome, multiple sclerosis, encephalitis, and drug hypersensitivity.
A positive PCR result in a serum test is generally considered a sign of active infection because the virus has left the cells (either because of cell death or active replication).
ABOUT THE HHV-6 FOUNDATIONThe HHV-6 Foundation in a non-profit entity founded to encourage scientific exchange between investigators and to provide pilot grants for promising scientific and clinical research on the under- appreciated viruses HHV-6A and HHV-6B. The Foundation sponsors international conferences and supports scientists and clinicians seeking to clarify the role of the two HHV-6 viruses in disease. Feel free to take a look around, meet the Waverunners, and see how the foundation is being set in place, by building a softball powerhouse in Indiana! Nearly 100% of us have been infected with the HHV-6 virus by early childhood and have antibodies to it, and at least 30% of us have small but detectable levels of latent virus in our blood (Alvarez-Lafuente 2002 & Clark 1996), so the relevant questions are not whether you have the virus, but rather how much virus do you have, and is it active or latent?
PCR DNA tests can detect HHV-6 in the serum during primary roseola infections and in acute transplant reactivation. Researchers at the NINDS have determined from autopsy that bone marrow transplant patients with active or reactivated infections in the CNS tissue have very little HHV-6 in the spinal fluid or serum (Fotheringham 2007). As is the case with pathogens with low viral copy numbers such as HHV-8 and West Nile Virus, indirect evidence of the HHV-6 antibodies are easier to find than the HHV-6 virus itself. Another reason that it is so difficult to detect HHV-6 directly by PCR is that there is latent virus in many of our circulating white blood cells.
New assays are desperately needed to identify the kind of low-level chronic activation that has been found in mesial temporal lobe epilepsy and suspected in MS and CFS. Individuals vary in the way they respond to virus: some may not be able to generate antibodies due to a weak immune response.
At Stanford, Montoya uses antibody tests done by immunofluorescence or IFA to determine if a patient might qualify for antiviral treatment. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Direct detection of human herpesvirus 6 DNA in serum by the loop-mediated isothermal amplification method. The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent. On the other hand, single infections with either HHV-6 or CMV did not significantly impact outcome.
HHV-6 DNA levels were significantly higher in the resected tissue of epilepsy patients with sclerosis compared to those without it. Although nearly everyone is infected with HHV-6 in childhood, only a small percentage experience reactivation of HHV-6 later in life.
A positive result on whole blood, however, does NOT necessarily mean an active infection because most of us have tiny amounts of latent virus circulating in the blood (10-20 copies per ml).
If you have ever had a positive PCR test, it is possible that this is due merely to your ciHHV-6 status.
What do I do now?Depending on your test results, you might be a candidate for antiviral treatment.
Since the HHV-6A and HHV-6B can smolder in the brain and other organs without circulating in the peripheral blood or plasma, identifying chronic infection is a challenge.
However, they cannot determine reliably if a patient has a chronic central nervous system (CNS) infection that has reactivated because there is so little virus circulating outside of the tissues. This means that if the HHV-6 is chronically active in the brain tissue, it may be impossible to find any evidence of it in the peripheral blood or even the spinal fluid. Therefore elevated IgG antibody levels (above a threshold) may be the only indication of a reactivated chronic HHV-6 CNS infection.
Among the assays that hold promise for the future: nested reverse transcriptase testing (nRT-PCR) to look at whether the virus is active in the cells. Others may generate large numbers of antibodies to many pathogens, and some healthy individuals have high titers of HHV-6 IgG antibodies.
He uses the IFA test at Focus Diagnostics Laboratory and has established a minimum threshold for treatment.
In a primary infection, which typically occurs before the age of two, IgG antibody levels increase four-fold within several weeks. Transplant patients who are given drugs to suppress their immune systems after a transplant often get reactivated viral infections. Since so many healthy individuals have detectable levels of latent virus in their white blood cells, PCR DNA tests of whole blood are not useful unless the test is quantitative, and the absolute level of virus can be compared to a healthy population (Gautheret-Dejean 2002). Qualitative PCR tests are useful if done on serum or plasma and the detection of DNA in serum or plasma is considered evidence of active infection (Secchierio 1995). HHV-6B has been associated with febrile seizures, status epileptics and mesial temporal lobe epilepsy.

HHV-6 is notoriously difficult to culture and will not replicate unless the virus is stimulated with chemicals.
This technique of examining samples for messenger RNA is generally accepted as a gold standard for detecting active, vs.
Detection of viral protein in the peripheral blood or in biopsy tissue by putting infected cells on slides and then staining them with specific monoclonal antibodies. Detection of PCR-amplified DNA in an intact cell by hybridization after PCR by using a labeled probe. The most sensitive antibody test for active infection was available briefly to researchers in the late 90’s and has never made it into commercial production due to the difficulties in production; it was based on antibodies to the early antigen (EA) or a protein produced by the virus in the early stages of infection. This is a novel technique developed in Japan that allows rapid detection of HHV-6 DNA using simple and relatively inexpensive equipment already owned by most hospitals, making it suitable for rapid diagnosis of roseola (Ihira 2007). Antibodies that are recently produced have low avidity while those produced in the past have high avidity.
This technique can be used to identify early and late viral antibodies and is quite sensitive. Steve Jacobson at the NINDS has developed a novel method to differentiate active from latent virus using this new technology. Jose Montoya, an infectious disease specialist at Stanford University, uses IgG antibody tests done by IFA to determine whether patients qualify for antiviral treatment since PCR DNA tests are insensitive. Usually, latent virus in a healthy person can only be picked up by the more sensitive “nested” PCR on whole blood (such as the one used by Redlabs USA).
We pride ourselves on hard work, dedication, and improvement; while enjoying the game of fastpitch softball. HHV-6A & B viruses (especially HHV-6A) can migrate to the central nervous system and other organs away from the bloodstream. Furthermore, in many viral infections large numbers of virions spill into the plasma when the virus is replicating but this is not the case with HHV-6 since it is spread largely from cell-to-cell or directly through the cells walls. The net result is that very little of it ends up in the serum so PCR tests must be extremely sensitive to detect persistent HHV-6 infections once the acute phase is over.
In a 1996 study of HHV-6 in CFS patients, 89% of the patients with IgG titers of 1:320 and above were found to have active infections by culture (Wagner, Journal of Chronic Fatigue Syndrome). So looking at elevated antibodies to determine active infection is far from a perfect measure. He does not use ELISA tests that are offered at many labs (which report a number such as 0-20) because they are difficult to compare to the IFA values established in the literature, and because these assays cannot be used to monitor values over time.
Most pediatricians test for IgM antibodies to confirm a case of HHV-6 associated roseola or febrile seizures. The virus typically reactivates in the lungs or organ tissue and sometimes in the brain tissue causing CNS dysfunction including depression and cognitive problems. When the virus is found in the serum or plasma it is considered a sign of active infection.
Tests done on whole blood are not useful for detecting active infection because there is so much latent virus in the cells of healthy individuals.
HHV-6A has been associated with MS and chronic fatigue syndrome, and may be more prevalent in patients with HIV. It is not available at any of the large commercial laboratories due to its expense and the difficulty with false positives. Cells from the tissue are stained with HHV-6 monoclonal antibodies to determine which proteins were expressed at the time the biopsy was taken. This technique has been used in the study of MS and tissues; quantitative analysis of viral mRNA expression indicates that both normal white matter and lesions in patients had significantly higher HHV-6 expression suggesting a role in pathogenesis (Opsahl 2005).
Since the EA antibodies disappear rapidly after active infection is over (unlike the “late antigen” antibodies that persist for much longer), they may be a better predictor of active infection. However, evidence has shown that HHV-6 reactivation can occur occasionally, especially during times of stress, other illnesses, in response to acute allergic reactions or during immunosuppression. Positive-nested PCR tests for HHV-6, HHV-7 and CMV (as done at Redlabs) should not be interpreted to mean that you have an active infection as many normals have low levels of DNA from these viruses in their bloodstream. The most common antiviral drug in use is Valcyte, an oral drug given to patients who have compromised immune systems to prevent reactivation of CMV or HHV-5.
Our goal as a team is to develop as softball players and build character within ourselves as well as represent our communities as responsible and classy individuals. HHV-6A has been found to persist in the spinal fluid long after it has disappeared from the plasma (Caserta 1994).
Stanford infectious disease specialist Jose Montoya believes that the best evidence of smoldering central nervous system (CNS) infection is the IgG antibody to the virus, and not the virus itself.
Montoya is currently conducting a placebo controlled trial of Valcyte in symptomatic patients with elevated antibodies to HHV-6 & EBV.
In these acute reactivations, HHV-6B DNA can often be detected transiently by PCR in the whole blood and less frequently in the serum.
However, HHV-6 and EBV are very “cell associated” which means there is very little free virus spilled in the serum, even in an active infection.
This makes it impossible to differentiate latent from active virus in cells using whole blood. Unless extreme measures are taken, false positive results due to contamination can be a problem. It has been used at several academic and research laboratories, but no commercial laboratory, currently offers the test for diagnostic purposes Sensitivity can be an issue because messenger RNA can be degraded quickly if the RNA is not stabilized with a stabilizing solution immediately after the blood sample is drawn. It has been used in Finland to monitor transplant patients undergoing immunosuppression (Loginov 2006).
Pathologists can also differentiate A variant from B variant by using variant specific antibodies.

Katherine Ward in the U.K has used avidity analysis of HHV-6 antibodies in the identification of primary vs. Development of a real-time polymerase chain reaction assay for the diagnosis of human herpesvirus-6 infection and application to bone marrow transplant patients. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. Epub 2006 Jan 18., A reverse transcription-nested PCR assay for HHV-6 mRNA early transcript detection after transplantation.
Although there are no drugs that are FDA approved specifically for HHV-6, physicians routinely use Valcyte or IV drugs foscarnet or cidofovir. If these patients show a dramatic drop in antibody titers and an improvement in symptoms in response to Valcyte treatment, he will demonstrate conclusively that elevated IgG titers can be a sign of active infection and could be a reliable biomarker for monitoring patients. A fourfold rise in IgG titers or the presence of IgM antibodies are considered proof of active infection. Transplant physicians use qualitative PCR in the serum or quantitative PCR in whole blood to look for reactivation in these patients (Gautheret-Dejean 2002). There is one commercial lab in the US, Wisconsin Viral Research, that offers a rapid culture test. Kits for conducting HHV-6 Immunofluorescence Assay (IFA) are available commercially through BIOCELL Diagnostics, Inc, and others.
We encourage you to explore the resources at right to learn more about testing, treating, and identifying HHV-6 primary infection and reactivation. Other labs that offer the IFA test (which is reported as a titer such as 1:160 instead of a single number) include Specialty Laboratories and Medical Diagnostics Laboratory. We hope that physicians will be able to establish a threshold for what can be considered “active” infection. Valtrex may help prevent an HHV-6 reactivation but is not effective against an HHV-6 infection that is already active.Can you recommend a doctor?The HHV-6 Foundation cannot recommend a doctor. Elevated IgG Antibodies to HHV-6 cannot indicate with certainty that the infection is active, but high titers support a clinical diagnosis. IFA kits can be purchased for research purposes as well; BIOCELL Diagnostics, Inc, and a few other companies offer these kits for purchase by investigators.
The HHV-6 IgM antibodies are typically produced only with the primary infection, and not in subsequent reactivations. The variant detected is almost always variant B (>97%), which is different from other conditions such as MS where the variant detected is primarily variant A (Alvarez-Lafuente 2004). This is in contrast to other infections where free virus leaves the cell, enters the plasma and then infects another cell. A positive result demonstrates that the patient has virus in the cells, and it can determine the variant, but this test cannot tell a patient whether that virus was active or latent before it was stimulated in culture. Quest Diagnostics owns Focus Diagnostics so you may be able to get the Focus test through Quest.
Similarly, elevated EBV VCA (late antibody) titers also cannot indicate with certainty that an infection is active.
However repeat testing or a procedure called “sequencing the band” is advised to rule out a false positive. Many healthy individuals have latent virus in their cells that will activate when stimulated with chemicals.
Typically, only infectious disease specialists prescribe Valcyte, although several CFS doctors have started prescribing it for patients who have elevated antibodies to HHV-6 and EBV.I have been told that I have “chromosomally integrated” HHV-6 or ciHHV-6. However, EBV Early Antigen (EA) antibodies disappear rapidly after an infection is over, so elevated EBV EA antibodies do predict active infection.
Many physicians believe incorrectly that an adult with no IgM antibodies means that the infection must not be active. If you have a titer of 1:640 or above at Focus Diagnostics, then this raises the level of suspicion. It is easier to find the virus in whole blood than in serum, so this is useful for variant typing, but a positive nested PCR result in whole blood does not indicate active infection since many healthy individuals have latent virus in the cells that is detectable by nested PCR.
Consequence of transplant sixth herpesvirus encephalitis encephalitis significant consequence of transplant. If your test is NOT from Focus you need to ask your doctor to find out from the laboratory director how your value compares to the median of a normal population. The laboratory director should have these statistics from studies done to license the test. If you find out the answer, please send the Foundation an email, as we would like to start collecting this information. If your result is in the top 20% of a normal population, then this could be a clue that your HHV-6 is “active” instead of latent. Commonly seen among stem cell transplant patientshuman herpesvirus discovered commonly seen.
If the ELISA result states that you have >1 and are “positive” this usually just means that you have been EXPOSED to the virus, not that you have an active viral infection. Encephalitis, bone marrow information including symptoms, diagnosis, misdiagnosis, katz , name.

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