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Chronic Granulomatous Disease is one of those
conditions in which the ability of white blood
cells to kill invaders, mostly bacteria and
fungi is impaired.
It's impaired because normally cells are supposed
to make bleach in order to kill things.
The way bleach works here is a little complicated.
It's more like a signal than like an actual
killing agent.
That signal gets disrupted and when that signal
doesn't get sent right, the cells don't kill
bacteria and fungi properly.
What happens is that patients with CGD develop
bad infections, and those bad infections can
be serious and fatal.
In addition though, what makes these immune
deficiencies so complicated, is that, not
only do they get bad infections, they can
also get bad inflammatory problems.
By that, I mean things -inflammatory bowel
disease, inflammatory lung disease, some skin
conditions, all of which really are sometimes
referred to as autoimmune or autoinflammatory
type problems.
CGD is an inborn problem, so people have it
from the moment they're born.
Yet, it takes some time for it to show up.
Usually, in the more severe forms, it shows
up before one year of life in boys.
It can show up as an infection, can show up
as inflammatory bowel disease or severe diarrhea.
Sometimes shows up as problems with swallowing or with eating.
Then, some of the later manifestations can be -infections, diarrhea, failure to grow normally.
Usually, most cases are diagnosed in childhood
before about age five.
However, there are people who have milder
forms who show up later in life.
People can be diagnosed in adolescence, in
adulthood, sometimes even in late adulthood.
The oldest known patient who was diagnosed
with CGD is 69.
-CGD is a defect of neutrophil function and
not number.
Patients with CGD may have completely normal
neutrophil counts, and often they do.
You would not typically see a neutropenia
in patients with CGD.
However, the neutrophils don't function normally.
In the most severe forms of the disease, the
bacteria can be engulfed by the neutrophil,
but the neutrophil cannot kill the bacteria.
What this leads to is large granulomas, hence
the name, as well as pus pockets or abscesses,
which can be found in any organ, most notably
the liver, the lung, the skin.
This leads to bacteria that are walled off
but not killed.
Ultimately, those bacteria then find their
way, either into other organs or into the
bloodstream where they cause severe illness.
-Early diagnosis of CGD is very important
because there are fantastic drugs we have
now that we didn't use to have that can help
prevent a lot of these infections, and decrease
morbidity and mortality in these patients.
Now, with great antifungals, which have really
changed the way CGD is managed.
Patients are living longer, they're staying
healthier.
Also with early diagnosis, definitive curative
treatment such as bone marrow transplant,
is actually an option for some of these patients
depending on the circumstance.
Earlier transplant in CGD has far better outcomes
than later transplant, because you're catching
them early before they have liver abscesses
or other fungal infections that could make
transplant later complicated when they're
immunosuppressed for the transplant.
We have a patient right now at our hospital
who is diagnosed based on family history right
at birth.
He has been managed on fantastic medications,
including interferon therapy, as well as antifungals
and sulfa antibiotics and he has been completely
infection free for over a year.
I think the early diagnosis really made a
big difference.
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-Patients who present with CGD, especially
the boys who have the X-linked CGD, often
present early.
By 'early', it can mean, as early as infancy.
They can present with severe infections or
unusual infections.
Severe infections can be internal organs that
develop a bacterial infection or a fungal infection.
These can be in the liver, in the spleen,
in the kidneys, in the blood, and even in
the brain, like a meningitis.
Some of these infections are quite serious.
The children need hospitalization, IV antibiotics,
surgeries to remove the infected tissues.
It can be quite life-threatening right from
a young age onwards.
The reason it presents so early and so intensely
in those boys is because they only have one
copy of an X chromosome.
The copy that they have of that X chromosome
bears the broken gene.
They have no backup plan, so all of their
cells, all of their white blood cells lack
the ability to kill certain kinds of bacterial
infections.
Pediatricians should be alert for any patients
who have severe disease, severe infection,
what we call opportunistic infections, which
are unusual infections with organisms that
don't normally occur in healthy children.
These include fungi and unusual bacteria.
-CGD can present in a variety of ways.
The most common way that we pick it up or
start to think about CGD is a young child
that has an invasive infection.
That's usually due to one of the organisms
that we know are commonly seen in children
and adults with CGD.
There are a series of germs that we know folks
with CGD are very predisposed to infections
with.
The main ones are the bacteria, Staph aureus,
Staphylococcus aureus, and then there's a
mold called Aspergillus, and few other bacteria
called Nocardia or Serratia, and then Burkholderia.
That list, those five organisms actually caused
the vast majority of CGD related infections
in United States.
-I go back to the example of Burkholderia
cepacia.
If an immunocompetent patient showed up with
a low-grade fever and flu-like symptoms, I
would probably say, "Go home and drink lots
of water and drink chicken soup."
If a patient with CGD showed up with those
identical symptoms, I would tell them, "You
have to go to the emergency room, get a blood
culture.
I'm worried that you might have a Burkholderia
cepacia bloodstream infection that could kill
you very quickly."
-Traditionally, we thought that the female
carriers of X-linked CGD were relatively asymptomatic.
It's true that an X-linked affected boy could
have developed his disease from a de novo
mutation, but usually, the treat is inherited
from his mom.
There's much-growing evidence to show that
these female carriers are quite symptomatic.
A recent work from the NIH showed that when
they're enzyme activity, their oxidative burst
drops below 20%.
They are at increased risk for developing
the same kinds of infections complications
that the X-linked CGD boys can develop.
What's also been shown, however, by multiple
groups throughout the world, is that these
X-linked carrier females can start developing
autoimmune disease even when the amount of
the respiratory burst is still above 20%.
Why this is?
We don't know, but we do know that the respiratory
burst, which is related to inflammation and
the protection from free radical, that's no
big surprise then that when something goes
awry in the system, that autoimmune complications
occur.
-Other unrecognized complications of CGD are
the autoimmune complications.
These patients can present with vasculitis
and granulomas almost anywhere in the body,
in terms of a Crohn's like colitis, pyloric
stenosis from granulomas in the pylorus, granulomas
in the vocal cords, in the sinuses, in the
lungs, in the bones.
The inflammatory complications related to
CGD often go unrecognized and misdiagnosed
as other granulomas as autoimmune syndromes.
Especially in the United States, since 70%
of the patients have X-linked CGD and are
boys.
Any patient, especially boys that present
with severe autoimmune complications should
be screened for chronic granulomatous disease.
Although, this is a rare disease, right now,
I think the statistics are about one in 250,000
in the United States.
It's not rare for the patients and it's not
rare for the patients family, it's what they live with.
It's important to keep CGD on the differential
for any of these inflammatory or infectious
complications, because the earlier that it's
diagnosed and the earlier that therapeutic
interventions can be implemented, the better
the outcome for the patient.
Early diagnosis, early intervention and treatment
in resolution of infection and autoimmune
complications are very key to the referral
for bone marrow transplant, because these
patients outcomes are better if they come
to transplant healthy without severe infection
or autoimmune complications.
Their lifelong survival is better if all of
these are under control, taken care of and 
diagnosed early.
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-Increasingly we're recognizing that abscesses
in other organs like a liver can be a very
serious complications in CGD.
This is being recognized as patients are living
longer with CGD, we're doing a better job
of antibiotic prophylaxis.
Even despite antibiotic prophylaxis, liver
abscess can emerge and tends to emerge in
patients with CGD.
We're still learning what the best treatment
approach is for those patients.
There is a significant morbidity associated
with abscesses of liver in patients with CGD.
-Whenever we're taking care of patients with
primary immunodeficiencies, a team effort is needed.
Oftentimes these children live far away from
the actual immunologists.
We immunologists, rely on the local pediatricians
to help us with the day-to-day management
of the patients.
That can include being able to see children
quickly when they present with fevers or other illnesses.
That can also include making sure that nurses
are available to teach the patients how to
use their medicines properly.
-There are a few aspects of caring for a patient
with CGD that are important to keep in mind.
Some unique features, this is a relatively
rare disease.
One of the things that's unique about it is,
this relatively small list of pathogens that
frequently cause disease in CGD.
Even though the neutrophil's a major component
of host defense, and even though the neutrophil's
involved in the clearance of many types of
organisms, it's really only about five pathogens
that cause the bulk of infectious disease
in these patients.
For that reason, we've been able to become
pretty effective with prevention of these infections.
-Lifestyle modifications matter.
Patients with CGD are most susceptible to
certain bacteria and certain fungus that can
be found in the environment.
We always caution our CGD patients that they
limit exposure to areas where certain types
of fungus or mold might come into contact
in the air.
Places like that are found in warm human environments
like barns or caves, or when houses are 
undergoing
renovation.
Our CGD patients should never be in those
kinds of environment.
The other place that we run into a lot, being
from Florida is freshwater and brackish water
specifically.
Brackish water is when saltwater and freshwater
meet.
The salinity can change of the water itself,
but certain bacteria grow in that environment
and can be very life threatening in CGD patients
should they become infected with those bacteria.
We caution our patients that they should not
swim in those environments.
Those are some of the considerations that
families have to take and healthcare providers
need to caution their patients about.
-The standard of therapy for patients with
CGD is to start on prophylactic therapies.
These have to be an antifungal, such as Itraconazole,
that's the one that's been most studied and
some kind of antibiotic that will help prevent
the development of Burkholderia cepacia  and staph.
Most commonly in patients who are able to
tolerate, Bactrim is the drug of choice.
These are for standard management.
The other thing that we recommend is that
they have frequent exams followed up at a center.
Frequent imaging, even though people worry
about the exposure of radiation, given that
a lot of patients end up with asymptomatic
fungal infections or pneumonias of considerable
size, we think that prophylactic imaging is
of benefit.
-The third element in the triad of things
for prophylaxis for CGD patients is gamma interferon.
There was a double-blinded study conducted
in 1989, which showed that that three times
a week use of gamma interferon can reduce
the frequency of infection.
To be fair we still don't know exactly how
it does that.
We think that it's in a very general way increases
the surveillance of the immune system, but
there's a price to pay.
Some patients may get fevers with this; although,
in most cases those fevers may subside over
long-term use.
Some patients may get nightmares, have trouble
concentrating and so on.
Although, there's a standard amount that's
recommended, at least at the NIH, we would
rather see someone take the gamma interferon
than not, and so we'll work with them.
We'll lower the dose, we'll lower the frequency.
Important to know that we don't have data
about what happens when you lower the dose
or lower the frequency in terms of protective
effect, but we think that this still provides
protective effect.
-Caring for patients with CGD can be difficult.
They get sick often and those infections can
be severe.
Having a team that helps care for these patients
is essential.
That includes primary care to check on general
health and be the first call if that patient
is concerned they have an infection.
Primary care physicians are going to need
support because these patients are rare and
it can be difficult to anticipate what they
will do next.
Having immunology and infectious disease and
bone marrow transplant to offer full range
of care for these patients is essential.
In addition, having support services, including
home health and social work can help address
any barriers to care and help patients maintain
compliance with their prophylactic antibiotics.
I think one of the things the physicians need
to understand about CGD is, because it's so
rare a lot of patients can feel very isolated
in their diagnosis.
Helping patients feel that they are connected
to a community can be essential to helping
them accept their diagnosis.
Also making sure that they have access to
supportive services, to behavioral health
is really essential, especially as they become
older and become teenagers in transition to
young adulthood.
-Bone marrow transplant is a therapy that
can be used for some patients with Chronic Granulomatous Disease.
The process of bone marrow transplantation
involves replacing the bone marrow and the
immune system of the patient receiving the
transplant.
In the case of Chronic Granulomatous Disease,
it is a deficient immune system or white cells
that are important for fighting infection
that do not work well.
Through bone marrow transplant, we're able
to replace the patient's own bone marrow and
immune system with the bone marrow and immune
system from a donor, whose white cells work
correctly, have normal oxidase activity, and
will be able to eliminate any infections that
the patient may have.
Although, bone marrow transplant is curative
of Chronic Granulomatous Disease or CGD, we
do not use this modality for all patients.
With bone marrow transplantation, there are
a lot of risks that are involved that can
place the patient at risk for complications.
The decision at which patients need to go
to bone marrow transplant with Chronic Granulomatous Disease
requires discussion between the patient
and the multiple specialist, including the
bone marrow transplant physician, to decide
if a bone marrow transplant is really the
best option for patients with 
Chronic Granulomatous Disease.
-When we think about bone marrow transplant
and its risks and benefits, I think we have
to think about a few things.
We have to think about the status of the health
of the patient who's going to be getting the
bone marrow transplant.
We have to think about what the donor options
are that we have available to us.
Certainly, we see the best outcomes across
the board in almost every form of transplant
if the patient has a match sibling donor available.
Then coming in as a close second is when there
are matched unrelated donors.
Either adult unrelated donors who are full
matches, or cord blood unrelated donors who
are full matches.
It becomes a little more tricky when there's
nobody who is a full match to the patient
and we have to consider using a half-match
relative, which would typically be a parent
because our risks of Graphers Host Disease,
the more we're mismatched can become higher.
-Bone marrow transplantation in CGD has come
a long way.
Recently, as 10, 15 years ago is really considered
an experimental therapy for CGD.
Now, especially for X-linked CGD, it is considered
a standard of care.
For bone marrow transplantation, the success
rate of bone marrow transplantation is dependent
on a number of factors.
The first factor is finding an appropriate match.
If a patient has a full sibling they have
a 25% likelihood of being a full match.
The better the match, the better the outcomes.
Number two, the older that patients are the
less likely the transplant is to be successful.
That is typically due to a number of factors,
including a permanent end organ damage that
results from recurrent infections the longer you wait.
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-Gene therapy and the future of that as a
treatment modality for Chronic Granulomatous
Disease.
I'll just summarize by saying that, in the
past I don't think we had the kinds of vectors
that were either safe enough or effective
enough to make this a reality for CGD.
We're in a new era of gene therapy.
The use of what are called lenti virus factors,
which seemed to be very effective at getting
genes into the true long-term repopulating stem cells.
There've been some singular successes now
using lenti vectors for gene therapy in such
disorders as Wiskott Aldrich Syndrome, in
some of the inherited disorders of lysosomes
storage, and in adenosine deaminase scid.
Over the past couple of years, many groups
have been working toward developing lenti
vectors for the X-linked form of CGD.
I'm very fortunate to have collaborators in
the UK and across Europe, as well as across the US.
Many of us have gotten together to work on
a clinical trial of gene therapy using a particular
lenti vector that appears to be quite effective.
Some of this work has already been presented.
There'll be an abstract presentation at the
American Society for Gene and Cell Therapy
this May, in which some of the early results
of the combined European and US studies have
shown that we can in fact provide substantial
clinical benefit to patients with X-linked
form of CGD, in terms of long-term correction
of the hydrogen peroxide producing capability
of circulating neutrophils.
This is still highly experimental.
The making the vectors and the doing of this
is still quite complex.
It's not quite ready to be available to the
whole world, but I think that within the next
four to five years at most, gene therapy will
be an available treatment modality for patients
with the X-linked form of CGD.
We and others are focusing on the other kinds
of CGD, particularly the next most common
p47-phox-deficient autosomal recessive CGD.
Clinical trials are not open for that yet,
but we hope that perhaps in the next year
or two the trials for that form of CGD will
also be open.
We're pretty excited about this.
We like to be our own competitors.
Although, we are fans of the lenti vector
gene therapy for CGD, we are very excited
about the prospects of gene editing.
Which is a way of not using viral vectors
that just insert all over the genome, but
rather to actually repair the actual gene
that is a deficient in X-linked 
Chronic Granulomatous Disease.
There's been quite a bit of progress in our
lab and other labs at going in and using things
like CRISPR to specifically repair the gene
that normally makes the missing protein in
X-linked CGD.
We've also, in our lab, been looking and have
some success in the laboratory with CRISPR
gene editing at fixing the p47 form of CGD.
My hope is that we will have a competitive
methods over the next five or six years.
I hope is that one of them will be even better
than the other.
I can't say that lenti vector is going to
be replaced by gene editing, but it's our
hope that we have more than one way of approaching
gene correction of CGD.
As with any treatment or biologic our hope
is that all patients treated would have spectacular
success, but in reality, what we find is that
we have a percent.
Our hope is that we'll continue to see an
80 or greater percent rate of patients who
dramatically benefit from this gene therapy.
Where do I see the future standard of care
for CGD patients?
It's important that I emphasize the fact that
CGD patients vary.
Some have severe deficiencies in their oxidase
activity and their production of hydrogen peroxide.
Some make a significant amount of residual
hydrogen peroxide and may have mild forms
of the disease.
Some who have the mild form of the disease
in terms of production of oxidases may have
fewer infections, but surprisingly may still
have a lot of inflammatory problems.
I think that more and more, we're going to
tailor our standard of care to the specific
patients and come up with algorithms with
ways of analyzing what we do for an individual
patient and say, "This patient should just
stay on the prophylactic antibiotics and the
gamma interferon.
This patient should go to regular transplant.
This patient should now do gene therapy."
I think that the future that I see is one
in which we not only have new ways of treating
CGD patients, but better ways of judging which
patient should get what kind of treatment.
-Gene therapy is on the horizon and we ourselves
have a study ongoing looking at the effects
of gene therapy.
Then eventually, we think that gene editing
will play a role in treating patients with CGD.
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-Patients with CGD do really need a multidisciplinary
approach to take care of them.
They're not a patient that any one person
can take care by themselves.
I can tell you that at our institution, the
average person with CGD will have three or
four people interacting with them.
We have infectious disease doctors who are
in there helping us work up any fevers, any
new infectious symptoms.
They help us prescribe the antimicrobials
that are needed.
Oftentimes, GI doctors are involved because
of the inflammatory bowel disease.
Sometimes our urologists are involved because
of the granulomas that can happen in the genitourinary
tract system.
It really is a disease that can affect any
aspect of your body.
It really is a disease that there needs to
be a close-knit team that helps to take care
of that patient.
One of the takeaways would be is that there's
a lot of physicians that a patient may see.
Oftentimes these patients with CGD are quite
sick and nobody's able to quite put a finger
onto why they're so sick.
One of the important things is being aware
of this disease, being aware of the manifestations,
and then being able to get them to a place
that can make the diagnosis and eventually
treat the disease.
Being aware of the places that those are,
are really some of the takehomes in order
to help our patient outcomes.
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