Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995
Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995
Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone
 marrow transplantation (BMT) has been shown to be curative. However the risks of
 transplantation are high and not all patients with CGD may need to undergo this high risk
 procedure. This study will determine the long term medical condition and daily functioning of
 participants with CGD after a transplant and if possible, compare these results to
 participants who do not undergo a transplant.
Chronic granulomatous disease (CGD) is an immune deficiency where the neutrophils (a type of
 white blood cell that kills bacteria and fungi) do no work properly. Some individuals with
 CGD have neutrophils that do not work at all, whereas others have neutrophils that work
 partially, but not normally. In the past (over 20 years ago), most individuals with CGD were
 managed with antibiotics and antifungal medications alone. As the science of blood and marrow
 transplant (BMT) improved, some with CGD started to receive a BMT. It remained controversial
 whether individuals with CGD should receive a BMT or medical management alone (antibiotics,
 antifungals, and other treatments that do not include BMT).

 The aim of this natural history study is to better define the role of BMT compared to medical
 management of CGD. Specifically, what are the outcomes of BMT versus medical management
 alone, why do some individuals with CGD benefit from BMT, and what are the long-term outcomes
 of both approaches. Researchers are interested in how individuals with CGD who have no
 neutrophil function may differ from those with some neutrophil function, how the types of
 infections and inflammatory complications of CGD impact on survival and how BMT may improve
 these complications. There are also questions as to how the types of bacteria (called the
 microbiome) found in the gastrointestinal tract (colon, large intestine) of individuals with
 CGD influences certain inflammatory complications (such as colitis), and how BMT changes the
 microbiome in individuals with CGD. All of this will help doctors in the future to better
 treat patients with CGD.

 This study includes a retrospective (looking back into the past), cross-sectional (one time
 collection of information and/or research testing) and a prospective (looking from today and
 into the future) component. These are known as longitudinal studies (e.g., looking at
 information of participants over time).

 Persons with CGD who were born 1988 to the present day are eligible, regardless of whether
 they received a BMT (as long as the BMT was after 1995) or medical therapy only. Individuals
 who are newly diagnosed with CGD can also be enrolled and followed longitudinally (over
 time), to determine their outcome from the choice of therapy that is made. An important
 component of this study is the 'cross sectional' study, where participants with more than 3
 years of follow-up after transplant or diagnosis are asked to provide additional research
 blood work, and information is gathered regarding long-term transplant outcomes such as
 infections, graft-versus-host disease, autoimmune diseases, and quality of life. In addition,
 the participants will be asked to provide stool samples to allow investigators to look at how
 certain bacteria found in the gut (called the microbiome) affect complications of CGD, such
 as gastrointestinal disease. This will allow primary immune deficiency investigators/doctors
 to better understand the outcomes of different therapeutic approaches and to best design new
 treatments and clinical trials in the future for children with CGD.
Inclusion Criteria:

 -  Participant Inclusion Criteria (Part 1 - Longitudinal Analysis)

 -  CGD Patients Undergoing Transplant 1995 to Present with Birth Year In or After
 1988

 1. CGD Patients will be Defined by both Defective Neutrophil NADPH Oxidase
 Function and by Clinical History Consistent with CGD

 Patients must have both of:

 A functional assay demonstrating abnormal NADPH oxidase function (see A
 below); AND Clinical history consistent with CGD (see B below).

 *************************************************************************

 Patients must have both "A" and "B":

 A. Function: Assays of NADPH Oxidase Function

 I. Dihydrorhodamine (DHR) Assay:

 -  Blood sample was obtained at a time when patient was clinically stable
 and not critically ill, with control samples performed simultaneously
 indicating a qualified assay; and

 -  Assay unequivocally demonstrates CGD with an stimulation index (SI) SI
 < 35 or equivalent. Assay report, including mean fluorescence intensity
 (MFI) from unstimulated and stimulated samples and gating strategy,
 must be de-identified and provided. OR

 II. Nitroblue Tetrazolium Oxidation Test (NBT):

 o Diagnostic of CGD (reported as reduced granulocyte oxidative response).
 Report must be de-identified and provided. AND

 B. Clinical History: One or More of the Following:

 -  Severe and/or recurrent infection (liver, perirectal or lung abscess;
 pneumonia; adenitis; or osteomyelitis) due to, for example,
 Staphylococcus aureus, Burkholderia sp, Serratia marcescens,
 non-albicans Candida sp, Aspergillus sp or other mold; or Nocardia sp
 or other deep tissue infection characteristic of CGD

 -  Sterile granulomatous disease in respiratory, gastrointestinal or
 urogenital tracts; or Crohn's disease-like colitis

 -  A family history consistent with either X-linked or autosomal recessive
 CGD

 In cases where either functional assay (A) or history (B) is equivocal, one
 or more of the following may be used to confirm a diagnosis of CGD:

 C. Absent or significantly reduced in expression or abnormal size of any of
 the 5 phox components (gp91 phox, p47 phox, p22 phox, p67phox, and p40phox)
 of NADPH oxidase, by either:

 -  Western blot

 -  Northern blot OR D. Mutation in a gene encoding one of the 5 phox
 components (gp91 phox, p47 phox, p22 phox, p67 phox, and p40 phox) of
 NADPH oxidase that is predictive of a decreased or absent oxidative
 burst. (Nonsense, frameshift, or previously described missense mutation
 associated with CGD).

 Molecular Diagnosis is Desirable In addition, molecular diagnosis (gene
 sequencing and expression analysis) of CGD is desirable and should be
 performed when possible.

 2. Further Characterization of Oxidase Level, Longitudinal Study, Prospective
 Cohort Patients who are to undergo transplantation during the study period
 must be further characterized as oxidase-null or oxidase positive by level
 of oxidase production by either:

 -  DHR assay stimulation Index: where SI ≤ 2.5 will be classified as
 oxidase-null CGD. Those with SI > 2.5 will be classified as oxidase
 positive CGD. A single validated test that is accepted by the PID-CGD
 Review Panel is adequate, but testing on two occasions for validation
 is desirable. OR

 -  Ferricytochrome C reduction assay of granulocytes with O2 < 2.3 nmoles
 /106 cells/h classified as oxidase-null CGD. A single validated test
 that is accepted by the PID-CGD Review Panel is adequate, but testing
 on two occasions for validation is desirable.

 OR

 o Genetic sequencing reporting a mutation that is unequivocally associated
 to absent oxidase production. (e.g. null mutations) will be classified as
 oxidase-null CGD (See discussion in Appendix I for how family history,
 genotype and CGD mutation information will be applied to assigning patients
 lacking any quantitative oxidase activity measurements to residual
 oxidase-null or residual oxidase-positive groups).

 3. Longitudinal Study, Retrospective Cohort Patients who have already been
 transplanted will be included regardless of whether further characterization
 by oxidase level (or genotype/mutation data) is possible or not.

 -  Non-Transplanted CGD Patients with Birth Year In or After 1988 A non-transplant
 (conventional therapy) group of CGD subjects will be enrolled in the longitudinal
 study. The non-transplant subjects will be selected from the potentially eligible
 (retrospective) patient cohort with diagnosis of CGD treated with conventional
 non-transplant therapy. Participating sites will enter their entire retrospective
 cohort of CGD patients having birth year in or after 1988 into the registration
 cohort for this protocol. Baseline for both non-transplant subjects and HCT
 subjects for the purpose of comparing survival will be the year of birth.
 However, for non-transplant subjects, many of the detailed analyses such as
 infection and autoimmune complication rates will be assessed in the year
 preceding the date of last contact.

 -  Participant Inclusion Criteria (Part 2 - Cross-Sectional Analysis) To participate in
 the Cross-Sectional Analysis, patients must have previously been enrolled into the
 Longitudinal Analysis of Protocol 6903. All transplanted subjects in the
 Cross-Sectional Analysis are surviving and shall have at least 3 years of follow-up
 post-transplant to be included. Non-transplanted CGD subjects will become eligible for
 consideration for the Cross-Sectional Analysis if they were eligible and enrolled in
 the retrospective cohort of the Longitudinal Analysis, and if/when they are > 3 years
 post-diagnosis of CGD. Provision of written informed consent will be required for
 inclusion in the Cross-Sectional Analysis.

 Exclusion Criteria:

 -  Participant Exclusion Criteria (Longitudinal and Cross- Sectional Analyses)

 -  Presence of other primary immunodeficiency syndromes that do not meet the
 clinical and laboratory criteria for CGD.

 -  Rac2 Deficiency

 -  Myeloperoxidase Deficiency (MPO Deficiency)

 -  Glutathione deficiency

 -  Leukocyte adhesion deficiency syndrome

 -  Non-transplant subjects:

 -  The above exclusions pertain.

 -  In addition, non-transplant subjects will be excluded if the only assessment of
 oxidase function available is the nitroblue tetrazolium (NBT) test (a
 non-quantitative test).