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Residência Pediátrica; 2021: Ahead of Print.
Chronic Granulomatous Disease: a Case Report
Tathiana Silva de Santana Constantino
1
, Ekaterini Simões Goudouris
1
1
Instute of Childcare and Pediatrics Martagão Gesteira , Allergy and Pediatric Immunology - Rio de Janeiro - RJ - Brazil.
Correspondence to:
Tathiana Silva de Santana Constanno.
Instute of Childcare and Pediatrics Martagão Gesteira. Rua Bruno Lobo, nº 50, - University City of the Federal University of Rio de Janeiro, Rio de Janeiro,
RJ, Brasil. CEP: 21941-912. E-mail: tathiana.santana@yahoo.com.br
Abstract
Chronic granulomatous disease is a rare disorder characterized by genec mutaons that causes defects in the NADPH
oxidase of phagocytes, resulng mainly in higher predisposion to fungal and bacterial infecons that threatens life.
Our objecve, with this study, is to report a case of chronic granulomatous disease diagnosed in a paent followed in
a pediatric instute in Rio de Janeiro. A male teenage, presented while an infant with many recurrent, dicult to solve
cutaneous infecons. The paent evolved, as years passed by, with Mycobacterium tuberculosis hepac abscess and severe
fungal pneumonia, before conrming the CGD diagnosis. Currently, the paent is using the indicated prophylacc drugs
and his clinical condion is controlled. Early diagnosis aiming to start suitable anmicrobial and anfungal prophylaxis
is fundamental to achieve beer disease control and mainly to improve paents’ prognosis and quality of life.
Keywords:
Granulomatous Disease,
Chronic, Anbioc
Prophylaxis,
Opportunisc Infecons,
Immunologic Deciency
Syndromes.
CASE REPORT
Submied on: 12/01/2019
Approved on: 02/15/2020
DOI: 10.25060/residpediatr-2021.v11n3-231
This work is licensed under a Creave Commons Aribuon 4.0
Internaonal License.
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Residência Pediátrica; 2021: Ahead of Print.
INTRODUCTION
Chronic Granulomatous Disease (CGD) is a heteroge-
neous genec disease that aects about 1:200,000 people
living in the US, caused by defects in NADPH oxidase in
phagocytes ( phox )
1,2
. These defects result in the inability of
phagocytes to destroy certain pathogens, leading to recurrent,
oen fatal, fungal and bacterial infecons and the formaon
of systemic granulomas
3,4
.
The most common sites of infecon are the lungs, skin,
lymph nodes and liver
5
.
Its diagnosis consists of performing tests that measure
the funcon of intracellular digeson of phagocytes, such as
the dihydrorhodamine test (DHR) and is conrmed by geno-
typing studies
6
.
Disease control is achieved with anfungal and anmi-
crobial prophylaxis, in addion to mely treatment of acute
infecons
3,5
.
The descripon of the proposed case aims to elucidate
this rare disease, demonstrate the severity of the infecons
that it can cause, as well as point out the importance of ade-
quate control and follow-up of the paent, showing how the
good management of the disease contributes to the impro-
vement of the prognosis and quality of life.
CASE REPORT
A 14-year-old paent started follow-up at the immu-
nology service at a pediatric instute in September 2017, due
to recurrent infecons.
During the period of early childhood, he presented
several skin infecons that were dicult to heal, with frequent
use of anbiocs; at 10 years of age, a contact with a relave
with tuberculosis, developed a liver abscess caused by Myco-
bacterium tuberculosis , diagnosed through liver biopsy. On this
occasion, he received a six-month RIP regimen, with resoluon
of the condion; at the age of 12 years, he developed persis-
tent fever refractory to common anbiocs, signicant weight
loss and respiratory symptoms. He received the inial diagnosis
of community-acquired pneumonia complicated with pleural
eusion, and aer 10 days of intravenous amoxicillin- clavu-
lanate , fever persisted and progressed to deterioraon in
his general condion. cervical adenomegaly and hepatosple-
nomegaly. Examinaons revealed screening for TORCH, viral
hepas and HIV negave, non-reacve PPD, sputum AFB
(three samples) negave. Chest ultrasound compable with
pulmonary consolidaon, without areas suggesve of necrosis.
Aer 48 hours afebrile, he was discharged. One month aer
the fever returns, associated with pain in the right hemitho-
rax, producve cough and new weight loss. Readmied for
diagnosc claricaon and the hypothesis that the paent
had immunodeciency syndrome was raised. Computed tomo-
graphy of the chest was performed, with a tree-in-bud image,
ground-glass opacies, and a juxtacisural cysc image in the
apicoposterior segment of the le upper lobe, suggesve of
fungal pneumonia. Serologies for histoplasmosis , aspergillosis
and paracoccidioidomycosis were negave. Treatment with
itraconazole and amoxicillin- clavulanate was iniated , pro-
gressing with resoluon of the condion.
At 13 years of age, the paent presented with hidra-
denis suppurava in the right armpit, with fever refractory
to outpaent cephalexin. He needed a venous regimen with
high-dose oxacillin for resoluon.
Based on the paent’s history, immunoglobulin dosage,
lymphocyte prole and vaccine response were performed at
the specialized service, with normal results and altered DHR,
conguring the diagnosis of CGD. Prophylacc trimethoprim-
sulfamethoxazole was started in conjuncon with itraconazole.
Currently, the paent remains under follow-up, using the
prophylacc regimen, without having new infecous episodes
or new hospitalizaons.
COMMENTS
CGD was rst idened and described in the 1950s in
a 12-month-old child in Minnesota who presented with an
exuberant clinical presentaon, including chronic suppurave
lymphadenis, hepatosplenomegaly, pulmonary inltrates,
and dermas
7
.
Although its incidence varies according to ethnicity, its
esmate is 1 in 200,000 live births. The case paent is male,
and studies show that men are more aected than women
by a rao of 2:1, due to the predominant model of genec
transmission (X-linked disease)
7
.
The immune system is a complex system capable of
recognizing a wide variety of external agents through dierent
biological processes. The generaon and release of reacve
oxygen species (ROS) in the form of an oxidave burst repre-
sents the main mechanism by which phagocyc cells destroy
pathogens. On the other hand, defects in oxidave balance
are also implicated in the pathogenesis of inflammatory
complicaons, which can aect the funcon of various organ
systems. NADPH oxidase (NOX) plays a key role in the produc-
on of ROS, and defects in its dierent subunits lead to the
development of CGD
9
.
Acvaon of phagocyte NOX requires smulaon of
neutrophils and involves the binding of essenal membrane
and cytoplasmic subunits (p47
phox
, p67
phox
, p22
phox
, p40
phox
,
gp91
phox
), playing a key role in killing microorganisms on pha-
gocytes
8,9
.
The disease is caused by genes that aect one X-linked
chromosome or three autosomal recessive chromosomes
4
.
X-linked CGD is caused by mutaons in the CYBB gene, which
encodes the gp91
phox
protein; the autosomal recessive form
is due to mutaons in the CYBA gene (encoding p22 phox
protein), NCF1 (encoding p47 phox protein), NCF2 (encoding
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Residência Pediátrica; 2021: Ahead of Print.
p67
phox
protein) or NCF4 (encoding p40
phox protein
)
3
. Approxima-
tely two-thirds of CGD cases in the US are caused by mutaons
in CYBB. Mutaons in NCF1 are the second leading cause of
CGD
5,10
. X-linked CGD is more common in areas with miscege-
naon, while the autosomal recessive form is more common
in areas with a history of inbreeding
8
.
Taking into account the paent in the case, we assume
that he has an X-linked disease. Although we do not know
the genec origin of his relaves, we know that there is no
history of consanguinity in his family, in addion to having
been generated in a of the most mixed countries in the world.
Children with CGD have recurrent fungal and bacterial
infecons. Infecons are caused by catalase-posive micro-
organisms , and the most common sites are the lungs, skin,
lymph nodes, and liver. In North America and Europe, the
most frequent pathogens are Aspergillus spp., Staphylococcus
aureus, Burkholderia cepacia , Serraa marcescens , Nocardia
spp. and Salmonella. In developing countries, Bacillus Calmee
- Guerin (BCG) and Mycobacterium tuberculosis are important
pathogens. There are a variety of bacteria that are virtually
pathognomonic for the diagnosis of CGD ( Chromobacterium
violaceum , Francisella philomiragia , Granulibacter bethesden-
sis )
5,6
. It is observed that the paent in the case presented both
bacterial and invasive fungal infecons, aecng the main sites
menoned (lung, skin, liver). The pathogen Mycobacterium
tuberculosis , prevalent in Brazil, aected the paent, who
was a contact with a case of tuberculosis without adequate
treatment. This shows the importance of epidemiological data
in conducng the clinical case.
CGD has the highest prevalence of invasive fungal
infecons of all primary immunodeciencies, and Aspergillus
fumigatus followed by A. nidulans , the most common iso-
lated pathogens. Aer Aspergillus spp., Rhizopus spp. and
Trichosporon spp. are the fungi most commonly idened in
paents with CGD
5,6
.
Symptoms typically appear in the rst two years of
life, and the median age at diagnosis is 2.5-3 years of age
1
. In
this case, his nal diagnosis was made late, at the age of 14,
despite the inial symptoms having started in early childhood.
At the cellular level, CGD can be diagnosed by measu-
ring the ability of phagocyc leukocytes to form superoxide
or hydrogen peroxide
1
. Well-known assays for measuring
NOX acvity are the Nitro-Blue cytochrome c reducon test
Tetrazolium (NBT), both measure superoxide. The dihydroro-
damine-1,2,3 (DHR) test is a well-known study that measures
hydrogen peroxide in this context
2
, It is currently considered
the gold standard for the diagnosis of CGD
6
.
Posive ndings must be conrmed by an addional
test, such as genotyping or immunoblong
1,4
.
The paent’s diagnosis was conrmed by the DHR, but
genotyping was not performed as an addional test, due to the
diculty of performing this test in our country. Its performance
would be indicated, but not essenal for diagnosc denion.
Management of CGD is based on indenitely anfungal
and anbioc prophylaxis; early diagnosis of infecons; ag-
gressive management of infecous complicaons. Medicaons
recommended for use as they have been proven to reduce the
risk of serious infecons are trimethoprim-sulfamethoxazole
(SMX-TMP) (5mg/kg/day 12/12h) and itraconazole (5mg/kg/
day 24/24h)
1
. The use of IFN gamma as prophylaxis is sll con-
troversial
2,5,10
. Currently, several studies indicate the benet of
using steroids in conjuncon with anmicrobials to treat cases
of exacerbated inammaon
5
.
Hematopoiec stem cell transplantaon (HSCT) is well
described as potenally curave in CGD (>90%). Transplanta-
on as an early treatment opon has been gaining ground,
with high success rates, being benecial not only in prevenng
infecous and inammatory complicaons, but also in redu-
cing exposure to prophylacc medicaons
1,5,8,10
. It is the only
curave therapy for CGD
8
.
Gene therapy is an aracve alternave to HSCT, being
an opon for paents without compable donors. As gene
repair technology becomes more advanced, DNA eding using
the short palindromic repeat/CRISPR (CRISPR/Cas9) could be
used to repair defecve genes in cases of X-linked CGD. This
method of gene therapy has been shown to restore cellular
NADPH oxidase in vitro
1,8
.
Our paent has been using anmicrobial and anfungal
prophylaxis since the diagnosis of CGD for about a year, and sin-
ce then he has not had new episodes of infecon, proving the
eecveness of the indicated medicaons. During this me,
we were able to observe the improvement in the adolescent’s
quality of life during their outpaent consultaons.
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