In short
Human herpesvirus 6 encephalitis is a serious brain infection that primarily affects people with weakened immune systems. While most children are infected with the virus early in life without serious problems, the virus can reactivate later and cause dangerous brain inflammation in vulnerable individuals.
What is Human Herpesvirus 6?
Human Herpesvirus 6 (HHV-6) is a virus that belongs to the herpes virus family. There are two forms of this virus: type A (HHV-6A) and type B (HHV-6B). These two types are now recognized as distinct members of the herpesvirus family, each with different characteristics and effects on the body.
Type B is much more common and infects over 90% of children by the age of three. In children, HHV-6B typically causes a common childhood illness called roseola infantum (also known as sixth disease or exanthem subitum), which usually resolves on its own. Less is known about Type A, but it mostly infects adults and often does not cause symptoms. However, HHV-6A is more frequently associated with serious disease in people whose immune systems are not working properly.
The virus is present worldwide and is mostly transferred from mother to infant. After the initial infection, the virus remains dormant (inactive) in blood cells, the salivary glands, and the brain. Like other herpesviruses, HHV-6 establishes lifelong infections in the body.
Causes and Risk Factors
Encephalitis is inflammation of the brain. HHV-6 encephalitis occurs when the dormant virus reactivates and causes brain inflammation. This reactivation happens when the immune system becomes weakened and can no longer keep the virus under control.
Weakened immune systems can result from several conditions and treatments. The most common risk factors include HIV/AIDS, chemotherapy for cancer, organ or stem cell transplantation, and other medications that lower immunity. HHV-6 infection is a major cause of opportunistic viral infections in immunosuppressed people, particularly transplant recipients and AIDS patients. Studies show that HHV-6 reactivation occurs in 35% to 46% of all hematopoietic stem cell transplant recipients, with rates as high as 90% in those with umbilical cord blood transplants.
Among the complications that can occur when HHV-6 reactivates in immunocompromised patients, encephalitis is the most well-recognized and most feared. In transplant recipients, HHV-6 infection and reactivation may lead to rejection of transplanted organs and, in severe cases, death.
Symptoms
The symptoms of HHV-6 encephalitis differ between children and adults, and also depend on whether the person's immune system is working normally.
In children with primary HHV-6B infection (their first exposure to the virus), most experience high fever and a rash. Some children can also experience seizures, and infrequently, some develop encephalitis that shows up as irritability and behavioral changes. Most of these symptoms resolve by themselves within five to seven days.
Adults with HHV-6 encephalitis, particularly those who are immunocompromised, have different symptoms. These include:
- Fever
- Symptoms of graft rejection (in transplant recipients)
- Low sodium levels in the blood
- Confusion
- Forgetfulness and memory problems
- Behavioral changes
- Seizures
In immunocompromised patients, HHV-6 infection may present with neurologic or behavioral changes, with or without the classic rash. Prompt recognition in this population is essential to ensure timely treatment and prevent complications.
Sadly, infection with HHV-6 can lead to death in both adults and children, particularly in those with weakened immune systems.
How is it Diagnosed?
Diagnosis of HHV-6 encephalitis is based on several factors working together. The most important element is identifying the virus in the cerebrospinal fluid (CSF), which is the liquid that surrounds the brain and spinal cord. This fluid is obtained through a procedure called a lumbar puncture or spinal tap.
The diagnosis requires three main components: the presence of the virus in the cerebrospinal fluid, the presence of signs and symptoms suggestive of encephalitis, and the absence of other causes that could explain the signs and symptoms.
The virus is detected using a laboratory technique called polymerase chain reaction (PCR), which identifies viral DNA in blood or cerebrospinal fluid. However, detection of the virus alone does not confirm active disease, so clinical suspicion and symptoms are also important.
Other tests that support the diagnosis include routine blood tests, which may show anemia and signs of infection. Sometimes an MRI scan may show changes in the temporal lobes of the brain, particularly affecting areas called the hippocampus, and can help exclude other conditions. An electroencephalogram (EEG), which measures brain activity, can also support diagnosis and is particularly helpful in those with seizures.
Treatment
Treatment of HHV-6 encephalitis varies according to the clinical situation. In immunocompetent children with roseola infantum, treatment is supportive, meaning it focuses on managing symptoms such as fever with medications like acetaminophen and ensuring adequate hydration. These infections typically resolve without intervention and carry an excellent prognosis.
However, in immunosuppressed hosts with HHV-6 encephalitis, antiviral therapy is strongly recommended. The two antiviral medications most commonly used to treat HHV-6 encephalitis are ganciclovir (or its oral version valganciclovir) and foscarnet. A third medication called cidofovir has also been used, often in combination with either foscarnet or ganciclovir.
These antiviral medications are usually administered through a vein (intravenously) for at least 3 weeks. However, treatment duration can be extended depending on the individual's response to therapy. Studies of antiviral effectiveness suggest that foscarnet is the most selective inhibitor of HHV-6 in laboratory studies, though no drug has been officially approved specifically for HHV-6 treatment.
It is important to note that these medications can have side effects. Ganciclovir can affect the bone marrow and cause problems with blood cell counts (cytopenias). Foscarnet can harm the kidneys and cause renal failure. Cidofovir can also affect kidney function. Therefore, both blood count and kidney function need careful monitoring during treatment.
One case report described successful treatment of HHV-6 encephalomyelitis in an immunocompetent patient using cidofovir followed by ganciclovir, with the patient making a complete recovery. Close monitoring and adjustment of treatment based on the patient's response is essential.
Long-term Outcomes
Outcomes vary greatly based on immune status and severity of organ involvement. Early treatment improves prognosis, but even with treatment, HHV-6 encephalitis can have serious long-term consequences.
In immunocompetent children, HHV-6B infection typically resolves without intervention and carries an excellent prognosis, with most recovering completely within five to seven days.
However, for immunocompromised patients with HHV-6 encephalitis, the outlook is more serious. Research on long-term outcomes shows that persistent neurologic deficits associated with moderate to severe bilateral hippocampal atrophy (shrinkage of brain structures important for memory) were characteristic findings, despite prolonged antiviral treatment. This means that even with treatment, many patients experience lasting problems with memory and other brain functions.
Patients may need extensive rehabilitation after HHV-6 encephalitis. One patient story describes going into a coma for over a month, experiencing paralysis of the legs, requiring a catheter, and needing plastic surgery for complications. Recovery required learning to walk again and intensive therapy, though gradual improvement was possible over time.
HHV-6 encephalitis in transplant recipients is associated with significant complications and can culminate in rejection of transplanted organs and death. Interprofessional healthcare teams should maintain a high index of suspicion when evaluating immunocompromised patients for possible HHV-6 related disease to enable early diagnosis and treatment.
