Evaluation of Patients With Immune Function Abnormalities

This protocol is designed for the screening and baseline assessment of and collection of
research sample from patients with abnormalities of immune function as manifested by
recurrent or unusual infections, recurrent or chronic inflammation, or previous laboratory
evidence of immune dysfunction. Abnormalities of immune function may be inherited or may be
iatrogenic such as that following hematopoietic stem cell transplantation or other treatments
resulting in prolonged immune dysfunction. Blood and/or bone marrow cells may also be used to
investigate the utility of induced pluripotent stem cells (iPS) for immune cell derivation
and targeted gene correction. This is not a protocol to study or screen for human
immunodeficiency virus infection, though patients with HIV infection who may have other
causes for immune dysfunction are not excluded. First or second degree genetically related
family members (limited to mother, father, siblings, grandparents, children, aunts, uncles
and first cousins of an affected patient) may also be screened for clinical, in vitro and
genetic correlates of immune abnormalities. Healthy Volunteers will be enrolled as a source
of control blood samples for research testing, not to include genetic testing. Screening and
baseline assessment under the auspices of this study may be limited to two visits over one
year period, unless the patient has been determined by initial evaluation to require further
study at NIH or are ongoing long-term safety assessments as required by their participation
on a gene therapy or transplant protocol. Patients with documented immune dysfunction may
receive limited medically indicated treatment if that medically indicated treatment is
related to the abnormality of immune function under study, with such treatment limited to the
period of the one year baseline assessment indicated in this protocol. When screening and
assessment is complete, patients will be offered an opportunity to participate in another
study, or if there are no active studies appropriate for the patient, other options will be
suggested to the primary or referring physician.

This protocol will allow detailed investigation of patients with abnormalities of immune
function with up to one year of observation with the following goals:

1. To determine the degree, scope and cause of immune dysfunction;

2. To establish the pace and pattern of change in the disease process;

3. To determine the extent of organ involvement and damage from immune dysfunction.

This screening and baseline assessment is necessary to discover new causes of immune
abnormalities, to delineate epidemiology of immune deficiencies, to develop new diagnostic
and therapeutic tools, and to determine a patient's eligibility for other studies.

Lung MRI as a CT supplement in Infection Surveillance in Immunodeficiencies:

The routine use of computed tomography (CT) has increased substantially since its
introduction into medicine, which, in turn, has also increased the amount of radiation to
which individuals are exposed. This increased radiation is not without risk and is
particularly problematic in our primary immunodeficiency disease population, who require
serial imaging with chest CTs to manage pneumonia. Standard medical practice in this patient
population is to diagnose infection by obtaining a diagnostic CT and then repeating the CT
every three to four weeks until the lesion has resolved in order to guide the treatment
course.

Although the radiation dose at our institution has been reduced by a factor of four in the
last several years as a result of peak kilovoltage (kVp) reduction dose modulation and
iterative reconstruction; cumulative radiation exposure carries an increased lifetime risk
for cancer and reducing exposure should be in keeping with the mandate, As Low As Reasonably
Achievable (ALARA).

Magnetic resonance imaging (MRI), which does not expose the patient to any ionizing
radiation, has shown promise in detecting the obvious infiltrates secondary to cross
sectional ability and increasing resolution.

Previously, lung MRI had not been considered as a potential substitute for CT because of poor
signal- to- noise ratio (SNR) due to the low density of protons in lung parenchyma, the short
T2* relaxation time in the lungs secondary to air-tissue based susceptibility, and the
challenge of imaging over long scan times resulting in respiratory, vascular and cardiac
motion artifacts.

However, the recent development of MRI scanning techniques that provide an ultra short echo
time (UTE) along with oversampling of k-space center appear to overcome the above mentioned
drawbacks of MRI for imaging the lung/ chest.

For this protocol, we will use optimized versions of the MRI UTE pulse sequence on our 3T
clinical scanners to perform breath-hold (BH) coronal and BH and free-breathing axial images.
Our goal is to comprehensively evaluate the lung without additional radiation with a
clinically reasonable scan time of <30 minutes, especially with a proportionally high
percentage of young adults.

Subjects enrolled under 05-I-0213 with primary immune deficiencies may be considered for
participation in the sub study to evaluate the feasibility of novel MRI techniques compared
with standard CT imaging for pathology surveillance if they are undergoing medically
indicated CT imaging for the diagnosis or monitoring of infection.

- INCLUSION CRITERIA:

Patients:

- Patients with abnormalities of immune function as manifested by recurrent or unusual
infections, recurrent or chronic inflammation, or previous laboratory evidence of
immune dysfunction are eligible for screening and baseline assessment under this
protocol.

- Of particular focus of this study are patients with clinical features or medical
history suggestive of Chronic Granulomatous Disease (CGD), X-linked Severe Combined
Immune Deficiency (XSCID), Leukocyte Adhesion Deficiency 1 (LAD) or chronic Graft
versus Host Disease (cGvHD).

- There will be no limit due to age, sex, race, or disability.

- All patients must have a primary physician outside of the NIH.

- All patients will be required to have blood stored for future studies (such as but not
limited to the modification of cells into iPS cells), and/or other medical conditions.

Relatives of Patient:

- Relatives may be mother, father, siblings, children, grandparents, aunts, uncles, and
first cousins to a patient.

- There is no limit due to age, sex, race or disability.

- Must be willing to have blood stored for future studies and/or other research
purposes.

Healthy Volunteers must:

- Be a healthy adult of either sex and between age of 18 and 85 years old.

- Have a hemoglobin count of 11.

- Weight greater than 110 pounds.

- Not have any heart, lung, or kidney disease, or bleeding disorders.

- Not have a history of viral hepatitis (B or C) since age 11.

- Not have a history of intravenous injection drug use.

- Not have a history of engaging in high-risk activities for exposure to the AIDS virus.

- Not be pregnant

- Be willing to have their blood samples stored for future research and modified iPS
cells.

Patient Participants in the FDG PET-CT and/or FDG PET-CT/MR-PET Scan Study Must:

- Already be enrolled and eligible to participate on protocol #05-I-0213 Screening and
Baseline Assessment of Patients with

Abnormalities of Immune Function

- Be at least 8 years old

Must have clinical evidence for significant life-threatening infection that would be a
standard of care medical indication for diagnostic CT scan where the FDG PET-CT/MR-PET scan
would be performed in lieu of that indicated diagnostic CT; or have had a CT or MRI that
did not adequately indicate the anatomic extent, location(s) or intensity of the infection

- Must be capable of overnight fasting and stopping of any intravenous glucose or other
intravenous nutritional feeding for at least 12 hours before the FDG injection and
through the period of time required for the FDG PET-CT/MR-PET scans, because glucose
and insulin significantly inhibits uptake of FDG.

- Must be psychologically capable of remaining in the confined space of the PET-CT and
MR-PET instruments. Patient will remain eligible for FDG PET-CT alone if the subject
cannot tolerate the confines of the MR-PET instrument.

Patient Participants in Lung MRI as a CT supplement in Infection Surveillance Sub Study
Must:

- Have a primary immune deficiency and be enrolled under 05-I-0213.

- Be willing to sign a supplemental consent to undergo lung MRI.

- Be greater or equal to 12 years of age

- Need a medically indicated chest CT

- Be psychologically/physically capable of remaining in the confined space of the MRI
machine for at least 30 minutes.

- Be able to lay flat.

- Be capable of following breath-holding instructions.

EXCLUSION CRITERIA:

Patients:

- The presence of certain types of acquired abnormalities of immunity solely due to HIV,
chemotherapeutic agent(s), or an underlying malignancy could be grounds for possible
exclusion for a patient.

- In the opinion of the investigator, the presence of such disease processes may
interfere with the evaluation of a co-existing abnormality of immunity that is the
subject of study under this protocol.

- Pregnant

Relatives of Patient:

- The presence of certain types of acquired abnormalities of immunity solely due to HIV,
chemotherapeutic agent(s), or an underlying malignancy could be grounds for possible
exclusion for a relative.

- In the opinion of the investigator, the presence of such disease processes may
interfere with evaluation of a co-existing abnormality of immunity that is the subject
of study under this protocol.

Normal Volunteer not eligible if:

- Less than 18 years old or older than 85 years.

- Have viral hepatitis (B or C).

- Receiving chemotherapeutic agent(s), or have underlying malignancy.

- Pregnant.

- Have history of heart, lung, kidney disease, or bleeding disorders.

Patient Participants in the FDG PET-CT and/or FDG PET-CT/MRPET Scan Study Must Not:

- Have cancer or have had radiation or chemotherapy to treat a cancer in the past 5
years.

- Have diabetes or abnormal glucose tolerance.

- Weigh more than 299lbs (or 136kg) or cannot fit in the bore of the instruments.

- Are a women of childbearing potential, you must have a negative urine or blood
pregnancy test within 1days prior to having the FDG

PET-CT/MR-PET scans.

- If you have aneurysm clips, metal fragments in the eye, certain types of metal implants
or prostheses, a pacemaker or other permanently attached electronic devices that are not
marked MRI compatible you may not be able to participate in the MR-PET portion of the study

Patient Participants in Lung MRI as a CT supplement in Infection Surveillance Sub Study
Must Not:

- Be less than 12 years of age

- Have claustrophobia or require sedation to undergo an MRI.

- Have an implanted metal object in the body (i.e. aneurysm clips, metal fragments in
the eye) that is contraindicated for MRI.

- Be pregnant.

- Have a body habitus greater than MRI gantry size/weight limit.