Evaluation of Patients With Immune Function Abnormalities

Study Overview
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Brief Summary
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This study will evaluate patients with abnormal immune function that results in recurrent or unusual infections or chronic inflammation. This may include inherited conditions, such as X-linked severe combined immunodeficiency (XSCID), chronic granulomatous disease (CGD), and leukocyte adhesion deficiency (LAD), or conditions resulting from outside factors, such as graft-versus-host disease (GVHD). The information from this study will be used to establish the pattern and pace of change of the disease and to help develop new treatments. The period of observation and study following enrollment in this study may be for up to one year. In addition these studies may provide the medical information needed to determine eligibility for enrollment in other clinical study protocols and more prolonged follow up. Patients of any age with abnormal immune function who have recurrent or unusual infections, whose blood tests show evidence of immune dysfunction, or who have GVHD, XSCID, CGD or LAD may be eligible for this study. Patients' parents, siblings, grandparents, children, aunts, uncles and first cousins of any age also may be included. Healthy normal volunteers between 18 and 85 years of age are recruited as controls. Normal volunteers undergo a physical examination and provide blood, saliva, and urine samples for immune function studies. Patients' family members provide a medical history, have a physical examination, and give blood and urine samples, and possibly a saliva sample. The samples are used for genetic and routine laboratory studies. Investigators may request tissue samples, such as biopsy specimens, previously removed for medical reasons to be sent to NIH for study. Patients undergo the following tests and procedures: Medical history and physical examination. Blood and urine tests, including analysis for genes involved in immune disorders. Buccal smear (in some patients) for genetic studies. This involves scraping the lining of the mouth near the cheek. Specialized tests to evaluate specific conditions in patients who have an immune disorder that might affect lung function, gum infections or eye problems. These may include chest x-ray, CT scan, breathing function test, dental, eye, and hearing examinations. Follow-up visits of patients with immune problems may occur at 6 months and at one year after the first visit (or more frequently if medically required) to include: Medical history update Physical examination Follow-up on abnormal test results and medical treatments initiated at NIH Collection of blood, saliva, urine, or wound drainage samples for repeat immune function studies Tissue study of specimens removed for medical reasons at other institutions besides NIH

Detailed Description
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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: To determine the degree, scope and cause of immune dysfunction; To establish the pace and pattern of change in the disease process; 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.

Official Title
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Screening and Baseline Assessment of Patients With Abnormalities of Immune Function

Conditions
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Chronic Granulomatous Disease (CGD), X-Linked Severe Combined Immune Deficiency (XSCID), Leukocyte Adhesion Deficiency 1 (LAD), Graft Versus Host Disease (cGvHD)

Participation Criteria
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Eligibility Criteria
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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. Women of child-bearing potential, or who are pregnant or lactating, may be eligible and will only undergo tests and procedures, and/or receive medications for which data exists proven minimal risk to the fetus or child. Only diagnostic tests without radiographs will be performed. 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. Women of childbearing potential, or who are pregnant or lactating, may be eligible and will only undergo tests and procedures, and/or receive medications for which data exists proven minimal risk to the fetus or child. Pregnant females will undergo diagnostic tests without radiograph exposure. 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 greater than or equal to 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 women will not be allowed to participate in any procedure that may be dangerous to the pregnancy or the fetus, such as risk of radiographic studies. 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. Pregnant female relatives will not be allowed to participate in any procedure that may be dangerous to the pregnancy or the fetus. Healthy 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Volunteers<br>Healthy adult M/F 18-85 y/o.Hgb>=11.Wt>110 lbs. No heart,lung,kidney,bleeding disorders. No hep BorC since age 11. No IV drug use. No exposure to the AIDS virus. Not pregnant. | |
| Patients<br>Patients with abnormalities of immune function | |
| Relatives of Patient:<br>Relatives may be mother, father, siblings, children, grandparents, aunts, uncles, and first cousins to a patient. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish the pattern and pace of change of disease (frequency, distribution, type and extent of infections, inflammatory lesions and abnormalities of immune function) during a period of up to one year baseline assessment. | Identification pregression and pattern of disease over time | ongoing throughout study | 
| To establish the extent of organ involvement (infection and/or inflammation) and organ damage or dysfunction resulting from the abnormality of immune function. | Identification of severity of disease as it relates to immune function in PID | ongoing throughout study | 
| To determine genetic linkage and biochemical correlates of the patient s abnormality of immunity by study of first and second-degree related family members blood cells (buccal smears instead of blood for genetic studies in some individuals)... | Identification of genetic links and biochemical correlates of PID to clinical manifestations | ongoing throughout study | 
| To characterize the physiologic, biochemical or genetic basis of the abnormality of immunity. | Identification of the pathophysiology and genetic basis of abnormalities of immune function under study | ongoing throughout study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine a patient s eligibility for other studies. | Patient recruitment to treatment protocols | ongoing throughout study | 
| To assess the patient s ability to safely tolerate specific aspects of other diagnostic or therapeutic research protocols. | Patients tolerate treatment for PID disease | ongoing throughout study | 
| To establish a baseline assessment of the pace and extent of the disease before entering a therapeutic clinical trial. | Identification of best time with respect to disease process to place pts on a treatment protocol | ongoing throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infection, Genetic, Inherited Disease, Immunity, Chronic, Abnormal Immune Function, Recurrent Infection, Chronic Granulomatous Disease, CGD, X-Linked Severe Combined Immune Deficiency (XSCID), XSCID, Leukocyte Adhesion Deficiency 1, LAD, Healthy Volunteer, HV