Epstein-Barr virus (EBV) is a member of the human herpes virus family that infects more than
95 percent of the U.S. population. Most infections occur in childhood and cause no symptoms;
in adolescents and adults, EBV often causes infectious mononucleosis. It has also been
associated with certain forms of cancer. Chronic Epstein-Barr virus (CAEBV) is a rare
disease, primarily of children and young adults, that leads to life-threatening infections.
This study seeks to identify genetic mutations responsible for CAEBV. A secondary goal is to
learn more about the natural history of CAEBV.
The study will examine blood and tissue samples from up to 50 patients (age 2 and above) with
CAEBV and up to 150 of their relatives (age 2 and above). Autopsy samples may be included in
the study. Up to 300 anonymous blood samples from the NIH Clinical Center Blood Transfusion
Medicine will also be examined for comparison.
No more than 450 milligrams (30 tablespoons) of blood per 8 weeks will be drawn from adult
patients, and no more than 7 milliliters per kilogram of blood per 8 weeks will be drawn from
patients under age 18. Local health care providers will refer patients to the study and will
obtain the samples. Some patients may also be seen at the NIH Clinical Center. Those patients
will have a full medical history and physical examination, along with chest X-ray, blood
counts, blood chemistry, EBV serologies, and viral load. Other tests, such as CT scan or MRI,
may be performed if medically indicated. Patients will be asked to undergo leukapheresis.
In vitro tests on the blood or tissue samples will include analysis for proteins or genes
that are involved in the immune response; cloning of portions of patient DNA; transformation
of B cells with EBV; measurement of the ability of patient blood cells to kill EBV-infected
cells; determination of lymphocyte subsets; and determination of antibodies to EBV or other
If a genetic cause for CAEBV is found, the investigators will be available to discuss the
results with patients in person or by telephone. Genetic indications of risk for other
diseases will also be discussed with patients.
Patients with chronic active Epstein-Barr virus (CAEBV) have (a) an illness that began as a
primary infection with EBV or markedly elevated titers of antibodies to EBV, (b) histological
evidence of organ disease, and (c) elevated EBV DNA levels in the blood or EBV DNA or
proteins in affected tissues. This is primarily a disease of children and young adults. Many
of these patients develop hypogammaglobulinemia or pancytopenia and death is frequently due
to opportunistic infections or B or T cell lymphoproliferative disease. The primary goal of
this study is to identify genetic mutations responsible for CAEBV. The secondary goal of this
study is to learn more about the natural history of CAEBV. Blood samples or available tissues
(e.g. previous biopsy or autopsy material) from patients with CAEBV and their relatives will
be analyzed to identify disease genes that are mutated in this population. In addition, some
of the patients will be invited to come for evaluation at the NIH Clinical Center. At that
time medically indicated studies of disease progression will be performed. Serial virologic
and immunologic studies will be performed. Eligible relatives of patients will be studied to
compare the gene(s) associated with CAEBV in patients with the gene(s) in their relatives.
Knowledge gained from this study has the potential of providing insights into the immunologic
control of EBV infections. In addition, identification of the molecular mechanisms for CAEBV
may provide insights leading to improved treatments for this disease.
- ELIGIBILITY CRITERIA
Study size: up to 150 patients
Sex distribution: male and female
Age range:no minimum nor maximum age
Patients with known or suspected CAEBV and their relatives will be recruited by referrals
from health care providers. The rarity of this disease will markedly limit the number of
patients available to study.
Patient recruitment is irrespective of racial and ethnic group or gender. NIAID
investigators will be available to answer questions and discuss general aspects of CAEBV
and identified genes or modifier genes with participants or their providers.
To be considered having CAEBV, a patient must have:
1. a severe progressive illness that began as a primary EBV infection, or associated with
postive EBV-specific antibody titers (IgG-VCA, ; EA or EBNA) not otherwise explained
2. evidence of major organ involvement such as lymphadenitis, hemophagocytosis,
meningoencephalitis, persistent hepatitis, splenomegaly, interstitial pneumonitis,
bone marrow hypoplasia, uveitis AND
3. detection of elevated levels of EBV DNA, RNA or proteins in affected tissues OR
elevated levels of EBV DNA in the peripheral blood
(a) Any other condition that, in the opinion of the investigator, would make the patient
unsuitable for enrollment or could interfere with the patient participating in the study.
RELATIVES OF CAEBV PATIENTS
Study size: up to 150 relatives of CAEBV patients
Age range: 2 years and above
To determine the genetic basis for this syndrome, the evaluation of blood, saliva and/or
previously obtained tissue specimens from healthy relatives of CAEBV patients will serve as
controls. No tissue biopsies will be performed on healthy relatives. We will
perform some or all of the studies listed in section V. on samples from normal relatives.
Study size: up to 300 persons
Age range: 18 years and above
Panels of anonymous blood samples will be obtained through NIH Clinical Center Blood
Transfusion Medicine to determine if identified genetic changes are mutations or