Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995

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).

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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).