A. Goussous, I. Habaibeh, K. Qaqa, N. Sunna, F. Haddad

INVASIVE PULMONARY ASPERGILLOSIS IN INFANCY:
A RARE PRESENTATION OF CHRONIC
GRANULOMATOUS DISEASE
Arwa N. Goussous MD*, Imad Habaibeh MD**, Kifah B. Qaqa MD*, Najwa W. Sunna MD*,
Fareed T. Haddad MD*
ABSTRACT
We report a rare case of chronic granulomatous disease in a three-month-old female infant who presented with a
chest mass, and was found to have invasive pulmonary aspergillosis and rib osteomyelitis, which was
confirmed by culture and histopathology. The diagnosis of chronic granulomatous disease in this patient was
made by the Nitroblue Tetrazolium test. The patient was successfully treated with surgery and antifungal
agents.
Key words: Chronic Granulomatous Disease, Aspergillosis, Immunodeficiency.
JRMS Dec 2007; 14(3): 57-60
Introduction
Chronic granulomatous disease (CGD) is a rare
disorder of white blood cells that results from
defective intracellular killing of catalase-positive
microbial species by phagocytes. (1,2) It occurs with
an incidence of 4-5 per million. (1) Approximately two
thirds of patients with CGD are males who inherit
their disorder as a result of mutations in the X-
chromosome, (a more severe form). (1) One third of
patients inherit CGD in an autosomal recessive
fashion. (1) The genetic defects result in failure of the
cytochrome b558 NADPH system to produce
superoxide, in the presence of normal B and T cell
function. (2) As a result of the defect in this key host
defense pathway, patients with CGD suffer from
recurrent life-threatening bacterial and fungal
infections. (3) The onset of signs and symptoms may
occur from early infancy to young adulthood. (1) The
most common pathogen is S. aureus, (1) but any
catalase positive microorganism may be involved,
such as Serratia marcescens, Pseudomonas cepacia,
Aspergillus Spp, Candida albicans, and
Mycobacterium tuberculosis. (1)
Case Report
A three month-old-female baby, the product of full
term normal vaginal delivery, with uneventful
pregnancy, presented in April 2003 with
asymptomatic right upper chest wall mass. The
examination was normal except for the right upper
chest wall mass measuring 5x6cm, which was soft in
consistency, mildly tender with no other signs of
inflammation. Initial work up showed an ESR of 70
mm/hr, a normochromic normocytic anemia, and
leukocytosis. Chest X-ray Fig. 1 showed right lung
upper lobe shadow, which was confirmed by chest
ultrasound. Chest ultrasound showed a soft tissue
mass 2.5x1.8cm extending deep to ribs of mixed
echogenicity with necrotic areas and increased
vascularity. Abdominal ultrasound was normal.
Chest CT scan Fig. 2 showed a large soft tissue
mass of mixed density measuring 5.5x5x4 cm in
dimensions, showing inhomogeneous enhancement
related to the right upper chest wall with extrathoracic
component and large intra-thoracic
component extending to the mediastinum. It encased
the branches of the aorta and downward to the right
hilar region where it compressed the right upper lobe
bronchus and probably the intermediate bronchus.
Associated destruction of the third and fourth ribs
was noted. In addition multiple different sizes of soft
tissue nodules were noted in both lungs.
From the Departments of:
* Pediatrics, Queen Alia Military Hospital, Amman-Jordan.
** Pediatric Surgery, Queen Alia Military Hospital, Amman-Jordan.
Correspondence should be addressed to Dr. A. Goussous. P. O. Box 2125 Amman 11953 Jordan, E-mail: arwamurad@hotmail.com
Manuscript received June 3, 2004. Accepted September 2, 2004.
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Fig. 1. Chest X-ray showing right upper lobe lung
opacity
Fig. 2. Chest CT-Scan showing right upper lobe lung
mass with bony destruction and extension to the
anterior chest wall
Fig. 3. Right upper lung lobectomy Fig. 4. Bone isotope scans showing 3 rd rib
osteomyelitis
Appearances suggested soft tissue sarcoma or
Ewings sarcoma with secondary metastatic
pulmonary deposits. Incisional biopsy was taken
with pus collection drainage. The specimen was
inconclusive, therefore an excisional biopsy was
decided, and a right lung upper lobectomy was done
(Fig. 3). Pathologic examination reported
necrotizing granulomatous pneumonitis with
fungal forms, and no evidence of malignancy.
Microbiological study of the specimens revealed
hyphae of Aspergillus Spp. Ziehl Nielsen stain for
acid fast bacilli was negative. Pus collection culture
showed Aspergillus Spp. The diagnosis of invasive
pulmonary aspergillosis (IPA) was made. A bone
isotope (Fig. 4) scan showed third rib osteomyelitis.
Brain and abdominal CT scans were normal.
Echocardiogram showed a normal heart.
According to this diagnosis, the possibility of
primary immunodeficiency disease was raised and an
immunological screen was done and showed elevated
IgG of 2126.9 mg/dl (700-1600), normal levels of
IgA, IgM, and IgE. T can B cell markers showed
normal distribution of T and B-lymphocytes and NK
cells. Sweat chloride was 22 meq/l. Nitroblue
Tetrazolium Test (NBT) showed 0% (both
unstimulated and stimulated) (N.R. for unstimulated
cells was 2-17% positive cells), HIV was negative,
and flow cytometry to measure oxidative burst was
unavailable in our institution. Based on the clinical
picture, investigations and the NBT test result, the
diagnosis of Chronic Granulomatous Disease was
made in this patient on April 2003. The patient was
treated with Amphotericin B and Trimethoprimsulfamethoxazole
(TMP-SMX) for 6 weeks. After
treatment the patient was discharged in a good
general condition on a prophylactic daily oral dose of
Itraconazole (5mg/kg) and TMP-SMX (10mg/kg
TMP). The parents are 2 nd degree relatives and there
is no family history of immunodeficiency disease.
Discussion
Patients with CGD characteristically have
lymphadenopathy, hypergammaglobulinemia,
hepato-splenomegaly, dermatitis, failure to thrive,
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anemia, chronic diarrhea, and abscesses. (1)
Nevertheless this was not the mode of presentation in
our case. Our patient was thriving well and presented
with a chest mass with invasive aspergillus
involvement of the lung and pleura that had caused
rib osteomyelitis and chest wall abscess with lack of
any other organ system involvement. Invasive
aspergillus infection usually involves pulmonary,
sinus, cerebral, or cutaneous sites. Rarely,
endocarditis, osteomyelitis, meningitis, infection of
the eye or orbit, and esophagitis occur. (4)
Segal and Holland (3) have looked into a national
database describing the spectrum of infections in 368
patients with CGD. They found that the commonest
pathogens include the Aspergillus sp. (pneumonia),
S. aureus (suppurative adenitis, subcutaneous
infections, and liver abscesses), Serratia sp
(osteomyelitis and pneumonia), Nocardia sp., and B
cepacia (pneumonia and sepsis). (3) Aspergillosis is
the most important cause of death in patients with
CGD. (3)
In the case presented here, based on the
radiological findings, the presumptive diagnosis of
malignancy was made. Nevertheless the final
diagnosis of IPA which had led to the diagnosis of
CGD in this patient was made after excisional
biopsy. Open or Thoracoscopic lung biopsies are
generally the "gold standard" in the diagnosis of
pulmonary problems in immuno-compromised
patients. (5) The diagnosis of IPA is best made by
demonstrating the presence of hyphae in the lung
tissue sample along with culture that is positive for
Aspergillus from the same side. Methenamine silver
nitrate and periodic acid-Schiff stains are the usual
stains to demonstrate the characteristic hyphae. (5) The
National Institute of Immunology, Allergy, and
Infectious Diseases has provided a working case
definition. The diagnosis of IPA is definite when
tissue histopathology shows the hyphae, with or
without a positive culture for Aspergillus from the
same site, or a positive culture from tissue obtained
by an invasive procedure such as transbronchial
biopsy, percutaneous needle aspiration, or open-lung
biopsy. (5) Serologic studies have no established value
in the diagnosis of invasive pulmonary
aspergillosis. (4) Other studies showed that the
Aspergillus galactomannan enzyme immunoassay
(GM EIA) may be a useful diagnostic tool for IA, but
its sensitivity is variable. Results demonstrated that
decreasing the index cutoff for positively to 0.5
increased its sensitivity with minimal loss of
specificity. The low cutoff increased the duration of
test positively before diagnoses by clinical means.
Therefore 0.5 cutoffs may allow for better
performance as an early diagnostic test. 6)
For screening of CGD, the Nitroblue Tetrazolium
(NBT) dye test is still widely used, but its rapidly
being replaced by the more accurate flow cytometry
test using dihydrorhodamine-123 fluorescence (DHR
test). (1) DHR detects oxidant production because it
increases florescence when oxidized by H 2 O 2 .
Surgical excision has been successful for some
cases
of pulmonary infection. Some clinicians emphasize
prompt surgery as a modality for centrally located
lesion (near the mediastinum) because of the higher
likelihood of catastrophic hemorrhage. There is
suggestion that surgical resection of isolated single
lesions is associated with better survival; however,
the presence of a single lesion itself is indicative of
early diagnosis and improved outcome compared
with multiple foci of disease. (7) In our case, surgery
has been beneficial, and has improved the prognosis
of the patient.
The largest therapeutic experience is with
amphotericin B deoxycholate, which should be given
at maximum tolerated doses. (8) Artiago FB (9)
described a case in which pleural involvement was
effectively treated with intrapleural instillation of
Amphoericin B. Responses to antifungal agents are
variable, and clinical response and overall mortality
are highly dependent on the hosts underlying
immune deficit at the time of diagnosis, clinical
manifestations, and whether immune-reconstruction
occurs during therapy. (7) TMP-SMX was added to
the regimen as a prophylaxis, (1) as well as
Itraconazole, which appears to be an effective and
well-tolerated treatment that reduces the frequency of
fungal infections in chronic granulomatous disease (10)
and because of its good penetration into bone. (8)
Treatment options for CGD in our patient are bone
marrow transplantation (BMT) and IFN-gamma
injections. (1) In a multicentric, randomized study
involving prophylactic IFN-gamma (50mug/m²
subcutaneously three times weekly) the number of
severe infections was reduced by more than 70% and
was beneficial in both the X-linked and autosomal
recessive types of CGD. (3) Bone marrow
transplantation is the only known cure for CGD. (1)
Some patients with CGD have been treated
successfully with bone marrow transplantation. (11)
Others may be treated by careful hygiene, preventive
antibiotics and injections if IFN-gamma. (11) The
mortality and morbidity rates associated with BMT
have discouraged its routine use the CGD patients.
BMT is most useful in patients who have had
recurrent severe infection despite antibiotics and
IFN-gamma prophylaxis. (3)
Invasive pulmonary aspergillosis is a serious and
rare entity, and the presentation of Chronic
Granulomatous Disease with a chest mass is even
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more unusual. Therefore CGD should be considered
in the differential diagnosis of chest wall mass and
failure to do so can lead to a delay in diagnosis and
prolongs morbidity. The patient is being followed up.
She is thriving well, with no major
immunodeficiency symptoms and is tolerating
treatment well. Her most recent follow up date was
on June 2004.
Acknowledgement
We would like to thank Dr. Adel Al-Wahadneh,
pediatric immunologist, for his help and support.
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