The Natural History of Severe Viral Infections and Characterization of Immune Defects in Patients Without Known Immunocompromise

Viral infections in the normal host are usually self-limited as the innate and acquired
immune systems mount successful antiviral responses. However, in some instances, apparently
immunocompetent persons manifest infections with viruses that would otherwise be observed
only in severely immunocompromised hosts. For example, cases of herpes simplex virus (HSV)
encephalitis, esophagitis orgastritis, cytomegalovirus (CMV) colitis, adenovirus hepatitis or
pneumonitis, recurrent or persistent skin infections caused by HSV or varicella zoster virus
(VZV), severe warts caused by human papillomavirus (HPV), recurrent respiratory
papillomatosis caused by HPV, severe influenza or respiratory syncytial virus pneumonia, and
progressive multifocal leukoencephalopathy (PML) due to JC polyomavirus have been described
in apparently immunocompetent patients. While a variety of case reports have described severe
viral infections in immunocompetent hosts, the pathogenesis of the vast majority of these
cases is not understood, and therapy can be unsuccessful.

In this protocol, we will evaluate patients without known immunocompromise, who have severe,
persistent, or treatment-refractory viral infections caused by herpesviruses, adenoviruses,
polyoma viruses, papillomaviruses, or other viral infections. We will investigate whether
certain host or virologic factors predispose these individuals to severe disease. We will
also determine the usefulness of various microbiologic tests (e.g., cultures, serology,
molecular assays) for following the course of infection in these patients. The physicians in
the Clinical Center will provide optimal therapy for these patients, as part of standard of
care. Identification of virologic or host factors that predispose these patients to severe
viral infections may have important implications for elucidating the pathogenesis of
infection and for the development of novel therapies.

- INCLUSION CRITERIA:

(Participants)

Participants must meet all the following inclusion criteria in order to participate in this
study:

1. Children or adults (regardless of age) without a known or fully defined
immunodeficiency and with a definitively diagnosed severe viral infection, including
infection caused by herpesviruses (HSV-1, HSV-2, CMV, EBV, VZV, HHV-6, HHV-7, HHV-8),
human papillomavirus (e.g., severe recalcitrant warts), adenovirus, polyomavirus (such
as JC virus and BK virus), or influenza virus. Viral infections that would be
considered "opportunistic-like", such as herpesvirus esophagitis, herpesvirus
encephalitis, CMV colitis, or progressive multifocal leukoencephalopathy (caused by
the JC polyoma virus), will be of particular interest in this protocol.

OR

Children or adults with a well-documented prior, severe, persistent, or treatment
refractory viral infection(s), who have clinically recovered from the viral infection.
If such a patient is not able to visit the NIH for evaluation, his or her personal
physician may mail-in blood or other clinical specimens to the NIH for analysis of
possible immune defects and for analysis of the virus for mutations, if indicated.

2. Ongoing care by a referring physician.

3. Willingness to allow storage of blood and tissue samples for future analyses.

(Relatives)

Relatives (2 years or above) may be recruited to establish the genetic origin of immune
defects that may be identified in the study subjects. We may obtain blood, buccal swabs or
a skin biopsy from the relatives.

1. Males and females will be accepted.

2. Adult relatives or the guardians of minor relatives must be willing and capable of
providing informed consent after review of protocol procedures that are described in
the consent form, with an appropriate study team member.

3. Participating relatives agree to have blood stored for future studies of the immune
system.

EXCLUSION CRITERIA:

Participants meeting any of the following exclusion criteria at baseline will be excluded
from study participation:

1. Patients with previously diagnosed conditions associated with immunodeficiency (e.g.,
a history of HIV infection or a positive test for HIV) or patients with conditions
requiring either daily systemic corticosteroids exceeding a dose equivalent to10
mg/day of prednisone or other significant immunosuppressant therapy (e.g., organ or
stem cell transplant recipients).

Note: Patients will be included if treatment with steroids or other immunosuppressive
medication was begun to reduce disease associated with the infection and instituted
AFTER the viral disease began.

2. Women who are pregnant.

3. Any condition or major comorbidity that the study investigators believe will
compromise the patient's ability to comply with the requirements of the study.