Genetic Studies of Chronic Active Epstein-Barr Disease
Genetic Studies of Chronic Active Epstein-Barr Disease
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 3 and above) with
 CAEBV and up to 150 of their relatives (age 1 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
 herpes viruses.

 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

 CAEBV PATIENTS

 Study size: up to 150 patients

 Sex distribution: male and female

 Age range: 1 year old and above

 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; therefore, we will enroll patients who are 1 year of age and
 older. However, children under the age of 3 years old will be enrolled as samples- only
 participants and not be evaluated at the Clinical Center.

 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: 3 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 of the studies listed 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.