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Rare Diagnosis in a Neonate Who Presents With Fever

Poneh Davoodi, Stephen Andrew Wright, Eric Vashon Brown and Jason Randall Perry
CLIN PEDIATR 2015 54: 91 originally published online 14 July 2014
DOI: 10.1177/0009922814541809
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research-article2014

CPJXXX10.1177/0009922814541809Clinical PediatricsDavoodi et al

Resident Rounds

Rare Diagnosis in a Neonate Who

Presents With Fever

Clinical Pediatrics
2015, Vol. 54(1) 9193
The Author(s) 2014
Reprints and permissions:
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DOI: 10.1177/0009922814541809
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Poneh Davoodi, MD1, Stephen Andrew Wright, MD1,

Eric Vashon Brown, BS1, and Jason Randall Perry, MD1

Case Report
An otherwise healthy 3-week-old African American
male presented to a pediatric emergency department
with a 1-day history of fever and tachypnea. He had
been in his usual state of health until the day prior to
presentation, when he developed a temperature of
38.9C and mild respiratory distress. His mother
reported increased fussiness, but he continued to feed
well and maintained good urine output. She denied any
other symptoms or any medication use. His only sick
contact was a 10-year-old cousin who had an upper
respiratory infection.
He was born at term via uncomplicated cesarean
delivery to a primigravid mother. He had an uncomplicated nursery course and was circumcised prior to discharge. Initially, no significant family history was
reported. The patient lives with his mother and does not
attend daycare.
On physical examination, his vitals revealed temperature of 39.7C, heart rate of 163 beats per minute,
respiratory rate of 30 breaths per minute, blood pressure
of 88/51 mm Hg, and oxygen saturation of 95% on room
air. He was alert and appeared in no distress. His lung,
cardiac, abdominal, skin, and neurological examinations
were all within normal limits.
Blood, urine, and cerebrospinal fluid (CSF) were
obtained. Initial erythrocyte sedimentation rate was 23
mm/h. Complete blood count revealed a leukocytosis of
20.9 103 cells/mm3, with a differential of 31% segmented neutrophils, 31% bands, 23% lymphocytes, 10%
monocytes, 2% eosinophils, and 3% reactive lymphocytes. Urinalysis was normal. CSF analysis revealed 1
red blood cell/mm3 and 8 white blood cells/mm3, with a
differential of 3% segmented neutrophils, 13% lymphocytes, 82% monocytes, and 2% macrophages. CSF glucose was 50 mg/dL, and protein was 26 mg/dL. CSF
enterovirus polymerase chain reaction and respiratory
viral panel were both negative.
Chest radiographs revealed opacities in the right
upper and middle lobes, and lingular regions that were
most compatible with multifocal pneumonia.

The patient was empirically started on intravenous

ampicillin 200 mg/kg/d and intravenous cefotaxime 200
mg/kg/d while awaiting the results of blood, urine, and
CSF cultures.

Hospital Course
He was admitted to the inpatient general pediatric wards
for concern of sepsis in light of neonatal fever with lung
opacities. Because of persistent fevers, pediatric infectious
disease was consulted and recommended the addition of
vancomycin and meropenem to broaden antibiotic coverage. Blood, urine, and CSF cultures were negative at 48
hours. A repeat chest radiograph revealed multiple, large,
bilateral nodular opacities. Because of these findings, a
computed tomography (CT) scan of the thorax without
contrast was obtained (Figure 1). This study revealed
numerous pulmonary nodules and masses scattered
throughout the lung parenchyma bilaterally, in a pattern
suggestive of a neoplastic process or atypical infection.
Several days after admission, his mother recalled a
maternal family history of granulomatous disease
affecting males that she forgot to mention initially.
These males died at an early age (Figure 2).
The patient then underwent CT-guided core biopsy of
the left lower lobe lung mass, and the specimen was sent
for bacterial, acid-fast bacilli, and fungal cultures. Given
the family history, a dihydrorhodamine (DHR) test was
also obtained and revealed an absent neutrophil oxidative burst, consistent with chronic granulomatous disease (CGD). Subsequent genetic testing revealed
mutation in CYBB gene. The lung biopsy revealed
microabscess formation with ill-defined granulomas and
fungal organisms consistent with the Aspergillus genus.

Georgia Regents University, Augusta, GA, USA

Corresponding Author:
Poneh Davoodi, Division of Allergy-Immunology and Rheumatology,
Georgia Regents University, 1120 15th Street, BG-1009, Augusta,
GA 30912, USA.
Email: ponehdavoodi@gmail.com

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Clinical Pediatrics 54(1)

Figure 1. Computed topography of the thorax. Numerous

pulmonary nodules and masses scattered throughout the
lung parenchyma bilaterally.

Figure 2. Family pedigree of our patient.

He was started on a treatment course of voriconazole

and improved throughout his hospitalization. Following
discharge, he received prophylactic trimethoprim-sulfamethoxazole and itraconazole, in addition to interferon
gamma as an outpatient. Ultimately, he would undergo a
bone marrow transplantation at an outside institution.

Final Diagnosis
Pulmonary aspergillosis in a patient with newly diagnosed chronic granulomatous disease.

Discussion
Chronic granulomatous disease is an inherited disorder
of phagocyte dysfunction that was first recognized in the

1950s. Currently, CGD affects nearly 1 in 200000 individuals, a majority of whom are males.1 The median life
expectancy of patients with CGD is 25 to 30 years with
a mortality of 1.5% per year.2 The X-linked variant
results from mutations in the CYBB gene on the X chromosome, which encodes the gp91phox component of
phagocyte oxidase, and is found in 65% to 75% of all
CGD patients.3 Mutation in CYBB was noted in our
patient. The autosomal inheritances affect the p47 phox
protein on chromosome 7, p67phox protein on chromosome 1, or p22phox protein on chromosome 16.3
Through further research, it has been found that the
defect lies in the nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase complex and results in an
inability to produce the superoxide anion or its metabolites of hydrogen peroxide, hydroxyl anion, or hypophalous acid. As a result, patients with CGD are more
susceptible to recurrent, life-threatening, catalase-positive bacterial and fungal infections, as well as granulomatous complications.4
Clinical manifestations of CGD manifest from early
infancy to young adulthood. The mean age of diagnosis
is about 3 years in X-linked CGD and about 7.8 years in
the autosomal variant.5 Males usually present earlier than
females, as expected, given the X-linked inheritance pattern. Patients with CGD typically present with recurrent
abscesses, pneumonias, cellulitis, lymphadenitis, osteomyelitis, hepatomegaly, and lymphadenopathy. The
majority of infections of CGD are because of the
Staphylococcus aureus, Burkholderia cepacia, Serratia
marcescens, Nocardia, and Aspergillus. Pneumonia
(usually Aspergillus) is the most prevalent infection,
affecting 79% of patients. The next most common infections are suppurative adenitis (53%), subcutaneous
abscess (42%), liver abscess (27%), osteomyelitis (25%),
and sepsis (18%). Salmonella is the offending organism
in the majority of cases presenting with sepsis.6 Patients
infected with bacterial and Nocardia species are usually
symptomatic with an increase in acute phase reactants
and leukocytosis, whereas patients infected with
Aspergillus species typically present with a lack of fever,
normal sedimentation rate, and fewer symptoms.7
The initial evaluation for a patient with suspected
CGD should include a neutrophil function test such as
the nitroblue tetrazolium (NBT) test or DHR 123. The
NBT test determines if there is any NADPH oxidase
activity in the neutrophil. Activated normal phagocytes
reduce yellow NBT to dark blue/black formazan and
forms precipitates in cells. The more recent test that is
used to determine NADPH oxidase activity is the DHR
test. The nonfluorescent dihydrorhodamine is phagocytosed and oxidized to produce a normal neutrophil
respiratory burst. This respiratory burst forms a green

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Davoodi et al
fluorescent compound that can be detected by flow
cytometry. The DHR test is able to distinguish between
X-linked and autosomal forms of CGD, whereas, the
NBT cannot. The diagnosis of CGD is confirmed by
using genetic testing.8
Our patient presented at an early age of 3 weeks. His
initial presentation included fever, tachypnea, leukocytosis, and mildly elevated sedimentation rate, which
were thought to be because of bacteremia and/or pneumonia. The family history of multiple male deaths was
crucial in leading to the diagnosis of CGD. Unfortunately,
this was discovered a couple days into the hospitalization. His abnormal DHR test and mutation of CYBB
gene confirmed the diagnosis. The Aspergillus noted on
CT-guided lung biopsy is consistent with the most prevalent infection found in this disease.
Trimethoprim-sulfamethoxazole prophylaxis is used
to decrease the frequency of bacterial infections.9 Our
patient was placed on this prophylaxis prior to discharge.
He was continued on voriconazole for treatment of
Aspergillus with plans to switch to itraconazole prophylaxis to decrease fungal infections, as proven by Gallin
et al.9 Treatment with subcutaneous recombinant interferon gamma has been shown to reduce the number of
infections in CGD by 70% compared with placebo.3
Bone marrow transplants have also been shown to be
successful in patients with CGD.4 Arrangements are
being made for our patient to undergo transplant. When
considering a bone marrow transplant, it is important to
consider the risk of transplant-related toxicity, such as
acute and chronic graft-versus-host disease.1

Conclusion
Chronic granulomatous disease is an X-linked or autosomal recessive primary immunodeficiency that leads to
recurrent bacterial and fungal infections. This case highlights the importance of a thorough history when evaluating a patient. The patient initially presented as a
neonatal fever and was admitted to the hospital for a
sepsis evaluation. After obtaining crucial information
about the family history and performing confirmatory
tests, the patient was diagnosed with X-linked CGD.
The defect in NADPH oxidase likely led to his infection

with Aspergillus. Although Aspergillus pneumonia is the

most common infection seen in patients with CGD, they
typically present and are diagnosed at a later age than
our patient who was a neonate at presentation.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.

Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.

References
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Bellanti JA, Escobar-Gutierrez A, Tsokos GC.
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MD: I Care Press; 2012. 569-573.
2. Marciano BE, Wesley R, De Carlo ES, et al. Long-term
interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004;39:692-699.
3. Kang EM, Malech HL. Advances in treatment for chronic
granulomatous disease. Immunol Res. 2009;43:77-84.
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