imaging pulmonary aspergillosis using 18f...
TRANSCRIPT
Abstract— Early clinical recognition of Aspergillosis
infection is difficult yet crucial to prevent fatal complications.
Various investigations play important role to confirm the
diagnosis. Positron Emission Tomography Computed
Tomography using flourodeoxy glucose (FDG) as biomarker
has a new role in imaging infection. In this study, we highlight
the potential role of this modality in the diagnosis of lung
aspergillosis infection. Methodology This retrospective study
highlights the semiquantifying value of aspergillosis lung
lesions through FDG PET/CT findings of 10 patients. The
final goldstandard in diagnosis is isolation of aspergillus sp
and/or a positive anti-aspergillus serological test. Results We
observed the findings from 7 males and 3 female patients
between the age of 48-80 (mean 66.8 SD ±9.3). Half of them
are elderly patients aged > 65 year old (range 48-80 year-old).
6 patients demonstrated underlying respiratory diseases like
chronic obstructive airway diseases, carcinoma of the lung and
chronic granulomatous infection like tuberculosis. Eventually,
the diagnosis of 8 patients were confirmed through isolation
of aspergillus sp while the other 2 final diagnosis were
confirmed through positive serological test. From the PET/CT
study, the mean semiquantification value of all lung
aspergillosis lesions by means of mean maximum Standardized
Uptake Value (mean SUVmax) is 4.25 (n=10; SD±1.904)
ranging between 1.64 to 8.30. Conclusion Pulmonary
aspergillosis infection demonstrate high metabolic activity
with SUVmax > 2.5 during FDG PET/CT study. The imaging
characteristic of lung aspergillosis infection in this study is
useful to navigate the clinical management.
I. INTRODUCTION
spergillosis lung infection can be contained where early
prompt treatment remains the critical prognostic factor
Abdul Jalil Nordin1, Noraini Abdul Rahim2, Zaid Fatah Azman1,3
C.E.Popescu4, G.Cabrini5, L.Minniti5, E.Gay4, C.Rossetti4 1Diagnostic Nuclear Imaging Centre , Universiti Putra Malaysia, Serdang,
Malaysia 2Radiology Department , Serdang Hospital , Malaysia 3Faculty Medicine Health Sciences , Universiti Putra Malaysia, Serdang,
Malaysia 4Ospedale Niguarda Ca’Granda, Milan Italy 5Centre of Molecular Bioimaging, University of Milano-Bicocca , Milan ,
Italy
(1). The common route for infection is through the respiratory
system where it can begin initially as lung infiltrates.
Aspergillus fumigatus and Aspergillus niger are the two most
common species causing lung aspergillosis infection (2). They
are often found to be complicating patients with underlying
immunocompromised situations or prolonged debilitating
disorders (3). Upon successful invasion, over a period of time,
aspergillosis lung infiltrate may advance into a fatal form of
angioinvasion and/or disseminated form. Thus early and
accurate diagnosis is desireable in arresting its progression.
Unfortunately, there is no single definitive test in establishing
the diagnosis. Combination of clinical informations and results
from laboratory studies are common management strategy but
time consuming and may be life treatening. Often, routine
serological tests for early detection not very useful due to its
low sensitivity (4). Positive yield from sputum cultures are as
low as 10%. Laboratory studies using biological and body
samples require invasive procedures and may be unsuitable for
chronically ill patients. Currently, non invasive cross sectional
imaging technique computed tomography has been the
mainstay imaging tool in the diagnostic work up of
aspergillosis infection (5,6,7). Recent effort in fine tuning its
performance by innovating an integrated system PETCT, a
combined modality has resulted in superior capability in
providing useful diagnostic informations from different
perspectives in a single seating. This technology advancement
improved the clinical management of patients with
malignancies resulting in effective treatment deliveries and
economy improvement. The initial course of direction for
clinical utility of PETCT in oncology is now widened into the
field of infections and inflammations (8,9,10). Thus the
established morphological appearance of lung aspergillosis
infection on CT may further benefit from additional metabolic
information provided by FDG tracer uptake.
This study tend to highlight the characteristic of aspergillosis
lung lesions in integrated Positron Emission Tomography
Computed Tomography using FDG as the biomarker.
II. METHODOLOGY
This study was conducted at The Department of Advanced
Technology, Ospedale Niguarda , Milan, Italy.
Retrospectively, 10 patients with discharge records confirmed
diagnosis of pulmonary aspergillosis infection between 2004
till 2009 were evaluated. During hospital admission, prior to
Imaging pulmonary aspergillosis using 18F-
Flourodeoxyglucose biomarker in Positron
Emission Tomography Computed Tomography
Abdul Jalil Nordin, Noraini Abdul Rahim, Zaid Fatah Azman, C. E. Popescu,
G. Cabrini, L. Minniti, E. Gay, C.Rossetti
A
Proceedings of the World Medical Conference
ISBN: 978-1-61804-036-7 210
antifungal treatment, all patients were thoroughly investigated
in confirming the diagnosis. Isolation of Aspergillus sp
organisme attempted in all patients from blood, tissue samples
and sputum. All patients underwent anti-aspergillosis
serological tests . Patients also underwent integrated diagnostic
imaging study using Positron Emission Tomography
Computed Tomography (PET/CT) with flourodeoxyglucose
(FDG) as tracer. A standard protocol prior to PET/CT image
acquisition was strictly followed. All patients were instructed
to be fasted for at least 6 hours prior to examination. Fasting
blood sugar level was ensured to be below 8 mmol/L for non
diabetic patients and 10mmol/L for diabetic patients prior to
intravenous injection of 8-10mCi of 18F-FDG. Image
acquisition was performed after not less than 45 minutes
duration of complete resting. This is to avoid soft tissue and
background FDG uptake which can reduce the sensitivity of
the study.
Studies were conducted using PET/CT Biograph equipment
with 4 slice multidetector ring. Imaging started with whole
body scanogram for planning. Low dose fine axial CT
transmission scan was first performed from the eyes to the
thigh for attenuaton correction and anatomical correlation.
This was followed by PET emission study 3 minutes per bed
position for 5-7 positions.
The results of FDG PET/CT studies were read by at least by
two experience specialists in PETCT . First, the MIP images
were analysed looking for focal areas of increase metabolic
activity on PET. This will be followed by detail analysis of
lesions found in 3-D reconstructed and CT attenuation
corrected axial, sagittal and coronal images. Concurrent
morphological CT changes on lesions were recorded. A region
of interest was manually drawn over any lesions found with
focal increase in metabolic activity to record the
semiquantification value. The above mentioned observed
parameters were tabled (table 1). The results were compared
with gold standard final diagnosis of aspergillosis infection by
isolation of Aspergillus sp including fumigatus, terreus, flavus
and or niger singly or in combination. Alternative confirmatory
test was achieved through one of the immunological study
including anti fungal antibody, PCE and/or PRIST studies.
III. RESULTS
All 10 patients who underwent FDG PET/CT study which
were conducted within 2 weeks of hospital admission. There
were 7 males and 3 female patients between the age of 37-80
(mean 66.8 ; SD ± 9.3). 60% of them had underlying
respiratory disease while the remaining 40% with no
underlying lung pathology.
Finally, the concluding diagnosis in all patients were
accomplished through isolation of aspergilus sp organisme or
positive serological test. Aspergillus fumigatus is the
commonest pathogen isolated observed in our study. No
organisme isolated in 2 patients. The final diagnosis were
ascertained through positive serological tests (table 1).
Figure 1 and figure 2 demonstrating two 18F-FDG PETCT
study with a foci of high metabolic activity in the posterior
segment (figure 1) and anterior segment (figure 2) of the left
upper lobe. The metabolic activity of the lesions matching the
upper colour scale in the left border of the images. White
arrows indicating the centre of lesion with raised metabolic
activity. 7 months following antimycotic treatment (image b),
a repeat 18F-FDG PETCT revealed partial (figure 1) and
complete (figure 2) metabolic response in PET with persistent
morphological CT appearance. The final outcome was
validated by negative serological test result.
Statistic analysis
From the results of lab and imaging investigations, there are
variety of observed parameters (table 1).
We devide our analysis into two catagories. In the first
category, we use the result of isolation of aspergillosis sp as
the “gold standard” (Table 2). In the second category, we
utilize the result of SUVmax for active lung aspergillosis
lesions where 2.5 was used as cut-off point (Table 3) .
Activities above the selected point were classified as ‘present
of infection’ while activities below the point were classified as
‘non infected lesion’. As a result, there were 9 concordant and
1 discordant findings in relation to the first category for
analysis. Aspergillus fumigatus isolated from 60% of cases
and Aspergillus terraus in 30%.
The mean maximum Standardized Uptake Value (SUVmax)
from our results of FDG PET/CT study is 4.25 (n=10) ranging
between 1.64 to 8.30 with a standard deviation of 1.90 (Figure
3). When we analysed the values of SUVmax based on
Aspergillus sp Isolation, there is no rank-difference in SUVmax
between those positive and negative cases (Table 2). Similarly,
when we analysed classification of SUVmax (cut-off value
>2.5) with Aspergillus sp isolation, we also fail to find
statistical agreement between the two (Table 3).
The SUVmax values were not normally distributed due to the
small sample size.
IV. DISCUSSION
The role of integrated functional and morphological imaging
modality Positron Emission Tomography and Computed
Tomography (PET/CT) using flourodeoxy glucose (FDG) as
biomarker is expanding into infections and
inflammation(8,9,10). Experiment conducted by Kubota
demonstrated in vivo high accumulation of macrophages and
granulation tissues as the reason for increased 18F-FDG
intratumoral distribution (11). Increased local hyperemia and
capillary permeability at the initial point of infection lead to
aegragation of inflammatory cells like granulocytes, leucocytes
and macrophage at the entry point. The resulting increased in
local glucose consumption is reflected by raised
semiquantitative uptake value (SUV) of all aspergillosis
infected foci except in one of our patients. In the evaluation of
FDG avid lesions, in addition to qualitative assessment
through visual intensity, lesional activity can be semiquantify
using standardized uptake value (SUV). The maximum SUV
or SUVmax is commonly employed in recording the metabolic
activity of FDG avid lesions. In our institution, like others , a
cutt off point of 2.5 is taken to differentiate between benign
and malignant condition. However, SUVmax should be use with
caution as it only indicate the ratio of FDG uptake in the whole
body and dependant on multifactorial parameters including
Proceedings of the World Medical Conference
ISBN: 978-1-61804-036-7 211
blood sugar, insulin level, body weight and tracer activities.
The detail is discussed elsewhere (12,13).
It is well known fact that fluorodeoxyglucose, being an
analogue of glucose molecule is a non-specific malignant
tracer. Avid FDG activity can be seen in benign and
inflammatory conditions. Chronic granulomatous infection
recently being proven to demonstrate intense 18F-FDG uptake
with SUVmax exceeding 2.5 mimicking malignant lesions
(14,15,16,17,18,19,20). Our findings further support previous
studies aiming at validating the quantification value of
SUVmax > 2.5 in active lung aspergillosis infection. We
validated our visually intense lesional activity in our patients
through positive isolation of aspergillus sp organism from
blood products and tissue samples and positive serological
studies. The metabolic information from combined PETCT
study using FDG as tracer can be an additional feature of
importance. An active aspergillus foci which show FDG-avid
activity can be an invaluable guidance for interventional tissue
sampling procedure avoiding wrong sampling sites for
isolation and cellular characterization (21,22,23,24).
In the past, Caillot D and his team (5) observed the usefulness
of CT in 36 netropenic patients with Invasive pulmonary
aspergillosis infection and found CT allow earlier diagnosis
thus developing a new strategy in clinical management of
pulmonary aspergillosis infection. His work was supported by
Kami M and his collegue (6) who concluded that chest CT
scan to be more beneficial than blood tests and X-ray for early
diagnosis of invasive pulmonary aspergillosis infection
through their study involving 215 patients 3 years later. The
result of our study has potential positive impact in amplifying
the present value of CT in the investigation of pulmonary
aspergillosis infection. Diagnostic CT can be performed as
part of integrated PETCT study to detect invasive ‘halo’ sign
which is proven to improved success rate up to 80% where
patients can be subjected to emergency pulmonary surgical
resection to avoid massive hemoptysis (25,26). With adequate
supporting evidence from clinical history and lab
investigations, the metabolic information gained during an
integrated PETCT study using FDG as metabolic marker, can
be utilized in guiding antifungal treatment . Initial SUVmax can
be used in evaluating treatment response (10,27,28). In
another study, Horger (29) observed that none of the early
HRCT manifestation of lung aspergillosis can predict
outcome. By incorporating metabolic information of FDG
PET into CT, the clue to outcome prediction can be resolved
and warrants future studies involving larger group of patients.
Our study has several limitations. It appears that, from our
preliminary findings, SUVmax fails to discriminate aspergillosis
infection from malignancy. This is apparent from analyses of
SUVmax in both rank and classified forms. However, low
power of observation is the main limitation of our study in
view of inadequate sample size. Thus, larger sample is needed
to address this problem. Another issue is that all analyses were
carried out in a pre-determined “gold-standard” . The
appropriateness of using our definition of ‘gold-standard” is a
clinical decision and is up for debate.
V. CONCLUSION
Active pulmonary aspergillosis infections is FDG avid on 18F-
FDG PET/CT examination. In an appropriatte clinical setting,
the metabolic information from combined PETCT study using
FDG as tracer can be an additional feature of importance to
guide interventionist during tissue sampling, navigating
clinicians in treatment and in future can be useful information
for outcome prediction.
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Table 1. Tabulation of demography data, underlying diseases and results of investigations
M: male; F:femae; TB:Tuberculosis; COPD:chronic obstructive pulmonary disease;p
Table 1. Tabulation of demography data, underlying diseases and results of investigations
Figure 1. A 52 year-old man diagnosed chronic pulmonary aspergillosis infection (image a) presented with recurrent dyspnea and cough. He showed positive serologic test to aspergillus specific Ig E aAnti mycotic treatment started and a repeat
No
Sex
Age
Predisposed
disease
1 M 77 Lung TB
2 F 48 COPD
3 M 60 nil
4 M 66 Asthma
5 M 67 Diabetes
6 M 64 nil
7 F 80 Lung TB
8 F 62 nil
9 M 70 Carc lungs
10
M
74
nil
Table 1. Tabulation of demography data, underlying diseases and results of investigations
COPD:chronic obstructive pulmonary disease;pos:positive;neg:negative:na:not available;
Table 1. Tabulation of demography data, underlying diseases and results of investigations
old man diagnosed chronic pulmonary aspergillosis infection (image a) presented with recurrent dyspnea and cough. He showed positive serologic test to aspergillus specific Ig E aAnti mycotic treatment started and a repeat 18F-FDG PETCT study was done after 7 months (image b)
Isolation Aspergillus sp
Immunology
Blood /
tissue/sputum Proven organism
anti AF
PCE/PRIST
pos/neg/pos Fumigatus pos/pos/neg
neg/pos/neg Neg pos/pos/pos
neg/neg/neg Neg pos/neg
neg/neg/pos Fumigatus pos/neg/neg
pos/neg/neg Fumigatus pos/neg
pos/neg/neg Terreus/Fumigatus pos/neg
pos/neg/neg Fumigatus pos/neg/neg
pos/neg/neg Terreus/Fumigatus pos/neg/neg
pos/neg/neg Fumigatus pos/neg
pos/neg/neg
Fumigatus
pos/neg
Table 1. Tabulation of demography data, underlying diseases and results of investigations
Table 1. Tabulation of demography data, underlying diseases and results of investigations
old man diagnosed chronic pulmonary aspergillosis infection (image a) presented with
recurrent dyspnea and cough. He showed positive serologic test to aspergillus specific Ig E and IgA antibodies. FDG PETCT study was done after 7 months (image b).
Immunology test FDG PET CT
anti AF ab /
PCE/PRIST SUV max
/pos/neg 6.16
pos/pos/pos 3.27
neg/neg 4.81
pos/neg/neg 3.26
pos/neg/neg 1.64
pos/neg/neg 3.81
pos/neg/neg 3.54
pos/neg/neg 2.73
pos/neg/pos 4.95
pos/neg/pos
8.3
Proceedings of the World Medical Conference
ISBN: 978-1-61804-036-7 214
Figure 2. A 45 year-old man diagnosed Chronic Pulmonary Aspergillosis confirmed by positive Aspergillusspecific Ig E and Ig G tests. 18F-FDG PETCT showed focal high metabolic activity in the left upper lobe (white arrows in image a). 7 months following antimycotic treatment (image b), metabolic response on PET with persistent bullae formation on CT in reswas validated by negative serological test result.
Aspergillosis
SUVmax Positive
Negative *not statistically significant (alpha set at 0.05), MannTable 2: Bivariate Analysis of SUV
SUV Max(<2.5) Negative
Positive
**not statistically significant (p-value=0.725, Kappa = Table 3: Test of agreement between SUV
Figure 3
old man diagnosed Chronic Pulmonary Aspergillosis confirmed by positive AspergillusFDG PETCT showed focal high metabolic activity in the left upper lobe (white
arrows in image a). 7 months following antimycotic treatment (image b), 18F-FDG PETCT revealed complete metabolic response on PET with persistent bullae formation on CT in response to treatment. The final outcome was validated by negative serological test result.
Aspergillosis N Mean Rank Sum of Ranks
9 5.33 48
1 7.00 7 *not statistically significant (alpha set at 0.05), Mann-Whitney U test.
Bivariate Analysis of SUVmax values vs. Aspergillus sp Isolation
Aspergillosis Isolation
Negative Positive
Negative 0 (0%) 0 (100%)
Positive 1 (11%) 8 (89%)
1 (10%) 9 (90%) value=0.725, Kappa = -1.11)
Test of agreement between SUVmax (Cut-off value >2.5) and Aspergillosis Isolation
Figure 3 . Distribution of SUVmax (n=10).
old man diagnosed Chronic Pulmonary Aspergillosis confirmed by positive Aspergillus-
FDG PETCT showed focal high metabolic activity in the left upper lobe (white FDG PETCT revealed complete
ponse to treatment. The final outcome
p-value
0.602*
1 (100%
9 (100%)
10 (100%)
Proceedings of the World Medical Conference
ISBN: 978-1-61804-036-7 215