Genetic Studies of Chronic Active Epstein-Barr Disease

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

CAEBV PATIENTS

Study size: up to 150 patients

Sex distribution: male and female

Age range: patients can be seen at the NIH Clinical Center age 3 or higher; mail in samples
can be obtained from persons of any 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.

Eligibility criteria:

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
AND

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

Exclusion Criteria:

(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: relatives of patients can be seen at the Clinical Center age 3 or higher, mail
in samples can be obtained from relatives of patients of any age.

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.

UNRELATED VOLUNTEERS

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
polymorphisms.