Chronic active Epstein-Barr virus disease (CAEBV)

Epstein–Barr virus (EBV) infects more than 9 in 10 adults worldwide. Usually it causes no symptoms, or it causes mono (infectious mononucleosis). In CAEBV, the virus lives in T cells or natural killer (NK) cells, two kinds of infection-fighting white blood cells, and these infected cells grow in number.

The illness looks like mono that does not go away. Japanese guidelines, updated in 2023, list four signs that must all be present. Mono-like symptoms last or keep coming back for more than 3 months. The blood or tissue has a high level of EBV. The virus is found in T or NK cells. And no other illness explains it.

Doctors now group CAEBV with the EBV-related growths of T and NK cells, next to the lymphomas. The World Health Organization calls it systemic chronic active EBV disease. Its older name was chronic active EBV infection.

The exact cause is not known. The infected T or NK cells are not cleared by the body’s killer T cells. Recent research suggests the virus may first infect early blood-forming cells in the bone marrow. As the infected cells grow, they pick up gene changes over time.

No single inherited gene change is known to cause CAEBV, and most recent reports do not describe more than one person with it in a family. It is most common in East Asia, including Japan. It is also seen in Mexico and in people of Central or South American descent, and less often in the United States and Europe. One study linked it to HLA-A26, a tissue type common in East Asia.

Some inherited immune disorders can cause an illness that looks like CAEBV. Some people were first thought to have CAEBV, but their virus was mainly in B cells. They were later found to have changes in genes such as the ones for perforin or GATA2. This is one reason doctors look for other causes before making the diagnosis.

Common signs are fever, swollen lymph nodes, and a large liver and spleen. In a study of 57 people with CAEBV outside Asia, 80% of those checked had low blood counts when they were diagnosed, and about two-thirds had liver problems.

Some people have skin problems first. In hydroa vacciniforme, blisters form on sun-exposed skin and heal with scars. In severe mosquito bite allergy, bites swell badly and can form deep sores. These skin conditions can progress to CAEBV.

Over time, CAEBV can cause HLH (a dangerous overreaction of the immune system), liver failure, inflamed blood vessels, and bulges in the heart’s arteries (coronary aneurysms). It can also turn into a lymphoma or leukemia of T or NK cells, sometimes many years later. In the group outside Asia, more than half had HLH and 40% developed lymphoma. Some people get worse quickly, while others stay stable for a time without treatment.

CAEBV is usually suspected when mono-like symptoms, such as fever, swollen lymph nodes and a large liver or spleen, last more than 3 months or keep coming back. Low blood counts and liver problems are common clues.

Japanese guidelines updated in 2023 require four things. These are symptoms for more than 3 months, a high amount of EBV in the blood or tissue, EBV found inside T or NK cells, and no other illness that explains it. They suggest a cutoff of 10,000 IU/mL of EBV DNA in whole blood. To find which cells carry the virus, labs can sort blood into B, T and NK cells and measure EBV in each. Or they can test a tissue sample (biopsy) for EBV RNA, called EBER.

Doctors also rule out other illnesses, including inherited or acquired immune problems, rheumatic (autoimmune) diseases and lymphomas. EBV antibody levels are often very high, but not always, especially when the virus is in NK cells. A 2026 expert review notes that tests to find the infected cell type are not standardized or sold commercially, which can slow diagnosis.

No medicine alone has been shown to cure CAEBV. In Japanese studies, chemotherapy alone rarely led to lasting remission, and none of 20 people treated with chemotherapy alone were alive 3 years later. Outside Asia, rituximab, a medicine that targets B cells, gave only a partial response in 8 of 25 people, and none of these responses lasted. That fits with the virus being in T or NK cells.

Medicines are used to calm the disease and lower the virus before a transplant. Japanese guidelines describe three steps: steroids, cyclosporine and etoposide (called cooling therapy); then lymphoma-type chemotherapy; then a transplant after reduced-intensity (milder) conditioning. U.S. experts may use high-dose steroids, or the antiviral ganciclovir combined with bortezomib or a histone deacetylase inhibitor, to buy time until transplant.

A donor stem cell transplant is considered the only cure. In Japanese studies, results were better when the disease was under control at transplant. They were also better in people younger than 15, and when the transplant came within 30 months of the first symptoms. Milder conditioning was linked with better survival than full-strength conditioning. After transplant, teams check EBV levels in the blood closely, because the disease can come back. Virus-fighting T cells from the donor may help treat a return.

Getting the diagnosis often takes months. Fever and swollen glands look like many other illnesses, and the tests that show which blood cells carry the virus are not widely available. In a Chinese study of 149 children, the median delay before diagnosis was 6 months. Outside Asia, some people were not diagnosed until an expert reviewed their case.

CAEBV is rare, especially outside Asia. Japanese guidelines say diagnosis and treatment should be carried out under the guidance of CAEBV experts. Treatment before transplant often means several rounds of medicines or chemotherapy.

After transplant, regular blood tests for EBV continue. In the group outside Asia, the disease came back in some people after transplant, and it was the most common cause of death after transplant. A few people needed a second transplant. In the United States, a National Institutes of Health study is looking for genes linked to CAEBV. Its record, last updated in July 2026, listed it as recruiting.

A transplant for CAEBV is allogeneic, which means it uses blood-forming stem cells from a donor. The goal is for the donor’s cells to rebuild the blood and immune system and clear out the infected cells.

The donor can be a matched brother or sister, another relative, an unrelated volunteer or cord blood. Outside Asia, only 12 of 49 donors were matched relatives, and 21 of 49 were unrelated. In a Japanese comparison, unrelated cord blood gave survival similar to bone marrow.

More than 9 in 10 adults carry EBV, and so did most donors: 35 of 36 donors tested in that group had it. All related donors in that group were tested for EBV. One related donor later developed an NK/T-cell lymphoma, which raised a question about shared inherited risk.

Joining a registry cannot promise a match for any one person. But many patients have no matched relative, and timing matters in CAEBV. In a Japanese survey, 18 people never reached a transplant because the disease got worse faster than a donor could be chosen and prepared. Volunteer donors and cord blood units make a transplant possible for more people.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

Without a transplant, CAEBV is usually fatal. In a Japanese survey, none of 20 people treated with chemotherapy alone were alive 3 years later. In a group of 57 people outside Asia, 6 of the 8 who did not have a transplant died of the disease.

A transplant improves survival, but its risks are real. Results are better when the disease is controlled before transplant, in younger people, and when the transplant comes sooner. With the Japanese three-step approach, 87% of 63 people were alive 3 years after a planned transplant. For people whose disease was active and uncontrolled, the figure was 17%.

Results differ by age and place. In Japanese studies, people whose illness began in the teen or adult years did worse than young children. Outside Asia, the disease often came back after transplant, and that was the main cause of death after transplant.