Human Herpesvirus 6

Human herpesvirus 6 (HHV6) is part of the Herpes family of viruses.  There are eight separate viruses within this family: Herpes simplex 1 and 2 (HV 1, HV 2), Varicella (HV 3), EBV (HV 4), Cytomegalovirus (HV 5), Herpes virus 6 (HV 6), Herpes virus 7 (HV 7), and Kaposi sarcoma-associated virus (HV 8) (1).  HV1 and 2 are most commonly associated with oral and genital herpes.  Varicella causes chickenpox and shingles and CMV causes CMV mononucleosis, which is similar to EBV mononucleosis but is often less severe. HV6 and HV7 are most commonly associated with roseola infantum.  HV8 is not a known cause of acute illness but may cause Kaposi sarcoma and AIDS-related non-Hodgkin lymphomas. (1)

Infection and Transmission

HHV6 exists as two variations, identified as HHV-6A and HHV-6, and the vast majority of infections, primary and reactivations, are due to HHV-6B. (2) After a primary infection, the virus becomes latent in the body and can reactivate later in life. (4)  It can remain latent in lymphocytes and monocytes, two types of white blood cells, and at low levels in organs. One of the primary locations is the salivary glands; “the virus replicates in the salivary glands and is shed in saliva, the recognized route of transmission.” (4)  Other routes of transmission, including transplacental/intrauterine and via breast milk, have been investigated but not been proven. (4)

Symptoms of Acute Infection

HHV6B is most associated with roseola infantum, an infection that occurs typically before three years of age; little is known about infections with HHV-6A. (2) Infections occur most commonly in spring and fall and HHV6 usually has an incubation period of 5 to 15 days after exposure. (3)  The first symptom may be a fever which begins “abruptly and persists 3 to 5 days without any localizing symptoms or signs. Despite the high fever, the child is usually alert and active.” (3) Swollen lymph nodes may develop and a rash appears primarily on the chest and abdomen after the fever subsides; rash may also be present on face, arms, and legs. (3)  The rash may be hardly noticeable in mid cases and “in 70% of HHV-6 infections, the classic exanthem (rash) does not occur.” (3)

Primary infection in adults is rare because almost 100% of people have been infected as children. (2, 4)  Adults can present with a mononucleosis-like syndrome (2) but the most serious symptoms occur in the immunocompromised, primarily organ transplant patients and patients with AIDS. (4)  “HHV-6 is considered a major cause of opportunistic viral infections (in these populations) in whom HHV-6 infection/reactivation may culminate in rejection of transplanted organs and death. (4)

However, similar to other viruses in the herpes family, symptoms can be wide ranging.  According to the HHV6 Foundation, “The following list is a summary of symptoms listed in persons with evidence for active HHV-6 infection:

• General Malaise: fatigue, chills, sweats, flu-like symptoms
• Cardiovascular: palpitations, tachycardia, arrhythmias
• Respiratory: oropharyngitis, coryza, cough, mild bronchitis, sore throat, intermittent wheezing
• Gastrointestinal: sialoadenitis, sicca syndrome, abdominal pain, indigestion, diarrhea
• Lymphatic: tonsillar hypertrophy, peripheral blood lymphocytosis, slight splenomegaly, mononucleosis-like disease
• Hematopoietic: anemia, thrombocytopenia
• Musculoskeletal: weakness, arthralgia, myalgia, SLE– or fibromyalgia-like symptoms
• Endocrine: various signs of thyroid dysfunction
• Skin: rash, eyelid & facial edema
• Central & peripheral nervous system: emotional lability, irritability, lack of concentration, headache, dizziness, loss of memory, chronic fatigue syndrome-type symptoms, paresthesia’s, peripheral neuropathy.” (5)

Complications of Acute Infection

Complications of primary HHV-6 infections are uncommon and rarely fatal. Case reports have described “invasion of the central nervous system (CNS) with seizures, hyperpyrexia, vomiting, diarrhea, cough, emophagocytic syndrome, fulminant hepatitis, disseminated infection, and hepatosplenomegaly. These complications suggest that the virus may spread to a number of organs, which may represent potential sites of virus persistence or latency and (subsequently) reactivation.” (4) HHV-6 has a strong “preference” to attack the nervous system and “neuroinvasion has been documented in infants with primary infection, in focal encephalitis, in children and adults with AIDS, in recipients of bone marrow transplants, as well as in immunologically competent children and adults.” (4)

Chronic Infection Concerns

Similar to EBV and CMV, there are several pathological conditions that have been linked to HHV6.  According to the HHV6 Foundation, “the relationship between HHV-6 infection and some of these diseases is well established (but) the role of HHV-6 in many other conditions remains unclear.  In addition to causing ‘acute’ disease, such as encephalitis, HHV-6 can also persist as a chronic infection, nearly undetectable by most current diagnostic tests. This subacute form of HHV-6 is likely to contribute to the pathology of many diseases associated with HHV-6.” 95)

This Foundation has a wealth of research and information on conditions possibly connected to HHV6, including the following list:

• “Autoimmune Diseases
• Cancer: Hodgkin’s Lymphoma, Gliomas, Cervical Cancer
• Chronic Fatigue Syndrome
• Cognitive Dysfunction: Delirium, Amnesia
• Colitis/Diarrhea
• Encephalitis/ Encephalomyelitis
• Endocrine Disorders
• Epilepsy: Mesial/Temporal Lobe Epilepsy, Status Epilepticus
• Heart Disease: Myocarditis, Left Ventricle Dysfunction, Arteriopathies
• Hemophagocytic Conditions: Hemophagocytic Syndrome/ Histiocytosis
• HIV/AIDS Progression
• Hypersensitivity: Drug Induced Hypersensitivity Syndrome (DIHS), Drug Reaction with Eosinophilia & Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS)
• Immune Suppression: Bone Marrow Suppression
• Kidney Disease
• Liver Disease: Hepatitis, HIV/AIDS Progression
• Lung Disease: Organizing Pneumonia, Pneumonitis
• Lymphadenopathy/Fever
• Multiple Sclerosis
• Rash & Roseola
• Seizures: Febrile Seizures, Status Epilepticus
• Transplant Complications: bone marrow suppression, Colitis/diarrhea, Delirium/CNS Dysfunction, Encephalitis/Amnesia, GVHD, Hemophagocytic syndrome, Hepatitis /Liver failure, Pneumonitis, Transplant Reactivation Overview
• Other Associations: SIADH, Hypogammaglobulinemia, Optic Neuritis, Microangiopathy, Mononucleosis, Uveitis” (5)

Reactivated HHV6 infection may also be present in inflammation of the blood vessels and collagen-vascular diseases and the implication of this association needs more research to identify if there is a possible causative effect from the virus. (5)

Diagnosis

Diagnosis of HV6 infection is typically based on clinical signs and symptoms of roseola in young children and testing is rarely done in these cases. (2)  Antibodies to HV6 can be tested to confirm diagnosis or if reactivation in suspected. (2)   Because almost 100% of people have had an HHV6 infection in childhood, the main issue for diagnosis is not if they are present, but if they are elevated beyond what would be expected.

Because HHV6 is primarily latent within cells of the body, the virus itself or viral DNA will typically be “detected in plasma only briefly during the initial infection or acute reactivation…detection of HHV-6 DNA in plasma generally means the patient has an active infection.” (7)  The HHV6 Foundation strongly notes that “a negative finding in the plasma does not rule out a localized active infection in an organ (e.g., uterus, brain, thyroid, liver).  Persistent HHV-6 infections have been found in the liver, brain, lungs, heart tissue, and uterus with no trace of HHV-6 DNA in the plasma.” (7)

There are two types of typical antibody testing for HHV6: ELISA testing and IFA testing.  According to the HHV6 Foundation, the ELISA test is less expensive than the IFA and is more commonly used by laboratories. (7)  For example, Quest Diagnostics Lab and Providence Labs only run the IFA for HHV6 IgG and IgM antibodies (8, 9) while LabCorp only runs the ELISA test.  (10) However, because the ELISA test was designed to indicate if antibodies are present, the HHV6 Foundation says that it is more difficult to use it to identify active infection since almost everyone will be positive on this test.  Indications for active infection can be gained from this test if the result is extremely elevated and there are clinical indications supporting possible infection. (7)   According to LabCorp’s information on interpreting results of the ELISA test in relation to the reference interval, “fourfold rises in titer are suggestive of either recent, primary, or reactivated infection. The presence of elevated titers to HHV-6 in the absence of responses to HAV, HBV, CMV, and EMV suggests that titer results are associated with high specificity.” (10)

The following table comes from the HHV-6 Foundation and provides a summary of the different types of testing for HHV6 and the general indications, advantages, and disadvantages of each test.

TEST	Can it differentiate active from latent infection?	Comments
ELISA IgG test Example: “positive >1.0”	No. These results are intended to give only “yes/no” answers to whether you are exposed to the virus in the past.	An ELISA> 5 in an adult MIGHT be a clue of an active infection, but only the antibody tests done by IFA can tell you with precision how elevated the antibodies are.
IFA IgG test Example: Titer 1:640	If the titer is highly elevated relative to healthy controls, it means that the patient may have had a recent infection or has a current chronic infection. Titers vary by laboratory. Focus Diagnostics (Quest) has a median antibody titer between 1:80 and 1:160 for controls. Other labs have much lower control titers.	If the patient has an immune deficiency with low total IgG, then the antibody titer will not be elevated. If HHV-6 is the only antibody titer out of five viruses to be elevated above average, then this indicates possible HHV-6 infection.
IgM test (ELISA or IFA)	Yes. IgM only appears during an active infection or for 2-3 months after an active infection.	The absence of an IgM antibody does not mean you do not have an active infection. Chronic infections in various tissues can persist with no evidence of IgM.
PCR DNA test on plasma or serum (qualitative or quantitative)	Yes. HHV-6 is never found in plasma or serum unless there is an acute infection (or the individual has ciHHV-6). However, the absence of HHV-6 DNA in the plasma/serum does not mean that there isn’t a low-level persistent infection in the tissues (e.g. heart, thyroid, brain).	Any positive test result should be repeated with a quantitative test. Also, a whole blood test should be ordered to rule out chromosomally integrated HHV-6 (ciHHV-6) which occurs in <1% of the population.
Quantitative PCR DNA test on whole blood Example: 1200 copies/ml	Yes. If the viral load is >200 copies per ml or 20 copies per microgram of DNA then this is an active infection.	Healthy persons will have very low viral loads, typically less than 20 copies/ml in the whole blood. Usually this level is not detectable in a commercial lab.
Qualitative PCR DNA test on whole blood Example: “Positive”  with no numerical value given	No. This test is useless for differentiating active from latent infection. Almost all healthy individuals have low levels of latent HHV-6B in the blood. On a sensitive nested PCR tests, at least a third of the normal population should test positive for HHV-6 latent DNA.	This test may be useful for determining if you have HHV-6A or HHV-6B but can’t tell you if the virus is active.
Immunohistochemistry  Staining of tissue sections from biopsies, mounted on glass slides.	YES. This test can tell you if the proteins expressed were from replicating virus. Only Coppe Labs and IKDT perform this service commercially.	This technique can also determine whether HHV-6A or HHV-6B is active. Analysis usually done on formalin fixed, paraffin embedded material.
Tissue Biopsy – qualitative	NO. This test cannot tell you if the virus is active. ViracorIBT offers a qualitative PCR test on tissues (liver, uterine, kidney, GI tract). Code: 6506	Depending on the lab, the virus can be typed. Specimens should be sent frozen overnight, with no liquid added.
Tissue Biopsy – quantitative	YES. This test can differentiate between low-level latent virus and active virus with high copy numbers. Coppe Labs and ViracorIBT (Code 6505) and can test tissues sent frozen in a sterile container.	Viracor requires 5 mg of material. Coppe can test 1 mg of material.   ”
ddPCR or Digital Droplet PCR to confirm ciHHV-6 status	This ddPCR test is done on whole blood and was introduced in 2013 by University of Washington specifically to identify ciHHV-6. It cannot identify active infection.	Patients should request this test when physicians want to confirm suspected ciHHV6.

Source: https://hhv-6foundation.org/patients/hhv-6-testing-for-patients

For the majority of patients, it appears that the IFA IgG is the best test to indicate active infection, and additional testing, including PCR testing for DNA and biopsies would be warranted only if specific symptoms indicated such.  If the ELISA test is the only one available, LabCorp’s interpretation guidelines may be useful.

Treatment

According to the Merck Manual, the “treatment of roseola infantum is generally       symptomatic. Foscarnet or ganciclovir has been used to treat some immunosuppressed patients with severe disease, but controlled trials are lacking.” (3)

Treatment of HHV6 reactivation needs to be assessed based on a patient’s current symptoms, test results, and concerns for possible development of future conditions linked to HHV6.  Because I see many patients with conditions associated with HHV6, I am very concerned about the developing body of research linking HHV6 as a potential causative factor for many of these diseases.

Disease occurs due to a combination of many different genetic and environmental factors.  Some factors, such as our genes, we cannot change.  There may be other factors medicine hasn’t identified yet.  Since these are areas we cannot treat, I look to those known environmental factors that are significant risk factors.   By reducing their impact, we can hopefully prevent future disease or reduce disease activity for those patients already diagnosed with these associated conditions.

Naturopathic medicine has many options for treating HHV6 both in terms of general anti-virals and options specifically designed for HHV6.  Levels of immune-essential nutrients, such as vitamin A, vitamin D and zinc, can be optimized. Monolaurin is a byproduct of coconut oil and is commonly used as a general anti-viral.  Lysine, which is often used to treat herpes simplex outbreaks, can also be used for HHV6, as can colostrum for patients who do not have issues with dairy.  There are numerous herbs, including olive leaf, garlic, goldenseal, Echinacea, and grape seed, and mushrooms, including cordyceps, turkey tail, shiitake, and lion’s mane, that can be used individually or in combination formulas.  Gemmotherapy preparations of several herbs are designed specifically to treat intra-cellular viruses, and essential oils can be added to herbal combinations.   Treatments can also include supporting the T-regulatory cells of the immune system, including probiotics, fish oil, vitamin D, and glutathione.

When using any of these therapies, it is important to start with low doses and increase slowly to patient’s tolerance.  Many people discuss “die-off” reactions with Lyme disease or candida overgrowth, and the same may be said for HHV6 infections.  As such, a complete plan would also include supports for detoxification and elimination, and would balance and rotate any anti-viral therapies.

Because these anti-virals are generally safe and well-tolerated, and the impacts of autoimmune disease can be devastating, this is one situation where I personally err on the side of treatment, especially in cases where patients have very high antibody levels and/or multiple high viral antibody titers.  My hope is that we can provide safe and relatively inexpensive treatment that could prevent a future health condition by treating a potential cause before symptoms arise.

Sources

• https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/overview-of-herpesvirus-infections
• https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-human-herpesvirus-6-infection-in-adults
• https://www.merckmanuals.com/professional/pediatrics/miscellaneous-viral-infections-in-infants-and-children/roseola-infantum
• https://wwwnc.cdc.gov/eid/article/5/3/99-0306_article
• https://hhv-6foundation.org/wp-content/resources/hhv-6-pictorial-atlas/3_Clinical_signs_and_symptoms.pdf
• https://hhv-6foundation.org/what-is-hhv-6
• https://hhv-6foundation.org/patients/hhv-6-testing-for-patients
• https://www.questdiagnostics.com/testcenter/TestDetail.action?ntc=34282
• https://www.testmenu.com/providence/Tests/666427
• https://www.labcorp.com/test-menu/28461/human-herpesvirus-6-hhv-6-antibodies-igg