Diagnostic value of 99mTc-ethambutol scintigraphy in tuberculosis: compared to microbiological and histopathological tests
Diagnostic value of 99mTc-ethambutol scintigraphy in tuberculosis: compared to microbiological and histopathological tests
A. H. S. Kartamihardja 0 1 2
Y. Kurniawati 0 1 2
R. Gunawan 0 1 2
0 National Nuclear Energy Agency of Indonesian , Jakarta , Indonesia
1 Faculty of Medicine , Universitas Andalas Padang, Padang , Indonesia
2 Department of Nuclear Medicine and Molecular Medicine, Dr. Hasan Sadikin General Hospital, Faculty of Medicine Universitas Padjadjaran , Bandung , Indonesia
3 A. H. S. Kartamihardja
Objective Tuberculosis (TB) still remains the world's endemic infection. TB affects the lungs and any part of the body other than the lung. The diagnosis of TB has not changed much over the decades. Ethambutol is one of the first line treatments for TB. It can be labeled using 99mTc. 99mTc-ethambutol will be accumulated in the site of TB lesion and can be imaged using gamma camera. The aim of this study was to evaluate the diagnostic value of 99mTc-ethambutol scintigraphy in detecting and localizing of TB. Methods Retrospective cross-sectional study was done. Subjects were patients suspected of having TB infection. Whole body and SPECT-CT imaging at the suspected area was done 1 and 4 h after injection of 370-555 MBq 99mTc-ethambutol. 99mTc-ethambutol scintigraphy was analyzed visually. The results were compared with that of histopathological or microbiological tests. Statistical analysis was done to determine the sensitivity, specificity, PPV, NPV and accuracy. Results One hundred and sixty-eight subjects were involved in this study. There were 110 men and 58 women with mean age of 34.52 ± 11.94 years. There were concordance results in 156 (92.86%) and discordant in 12 (7.14%) subjects between 99mTc-ethambutol scintigraphy and histopathological or microbiological result. The sensitivity, specificity, PPV, NPV and accuracy of 99mTc-ethambutol scintigraphy in the diagnosis of pulmonary TB were 93.9, 85.7, 93.9, 85.7 and 91.4%, respectively, for extra-pulmonary TB 95.5, 77.8, 97.9, 63.6, and 85.1%, respectively, and for total tuberculosis 94.9, 83.3, 96.3, 78.1 and 92.8%, respectively. There was no side effect observed in this study. Conclusion 99mTc-ethambutol scintigraphy is a useful diagnostic imaging technique to detect and localize intra- and extrapulmonary TB. It is safe to be performed even in pediatric patient. Consuming ethambutol less than 2 weeks did not influence the result.
Pulmonary; Extra-pulmonary tuberculosis; SPECT/CT imaging; 99mTc-ethambutol
Tuberculosis (TB) is an infectious disease caused by the
bacillus Mycobacterium tuberculosis. TB is not only
typically affecting the lungs known as pulmonary TB, but also
affects any part of the body as single or multiple sites known
as extra-pulmonary TB [
]. Tuberculous bacillus causes
a focal infection in the site where it is deposited after
]. TB remained one of the top 10 causes of death
worldwide. It still remains the world’s endemic infection
although between 2000 and 2015 the number of deaths fell
by 22%. The TB epidemic is larger than previously
estimated. There were an estimated 10.4 million incident TB
cases worldwide in 2015, while the rate of decline incidence
from 2014 to 2015 remained at only 1.5% although the
treatment averted a million deaths. This condition could be due
to persisting gaps between treatment and diagnostic
modalities. According to WHO report, one-third of pulmonary TB
was undiagnosed or delayed diagnosed caused continued
transmission in communities [
The diagnosis of TB remained unchanged for many
decades and it probably would have no progress. The ultimate
diagnosis of TB depends on the recognition of
Mycobacterium tuberculosis on histological examination and/or
bacteriological culture. Several diagnostic tests for TB have been
developed including sputum smear microscopy more than
100 years ago [
]. Unfortunately, the most of undiagnosed
pulmonary TB was cases with negative smear sputum
microscopic. A systemic review showed that the sensitivity of this
test is only 31–69% [
]. Molecular diagnostic tools have
been developed, but it cannot be routinely used for diagnosis
of pulmonary TB [
]. Currently, the Xpert® MTB/RIF
assay is recommended by WHO for the diagnosis of TB. The
test has much better accuracy than microscopy and culture
methods. The limitation of this test is requiring more
developed laboratory capacity and sometimes difficult to collect
adequate specimen. Other limitation is it takes 2 weeks to
provide results [
]. The diagnosis of extra-pulmonary
TB is more difficult compared with that of pulmonary TB.
Extra-pulmonary TB involves relatively inaccessible sites
for bacteriological confirmation as well [
]. In these
situations, rapid non-invasive imaging modality is necessary
to detect and localize the site of TB.
Nuclear medicine technique is a non-invasive
diagnostic modality which is highly sensitive and specific to detect
and localize the lesion at early stage and less time
consuming. A wide variety of radiopharmaceuticals have been
used for infection/inflammation imaging. 67Ga-citrate is a
high-sensitive agent for infection/inflammation imaging, but
non-specific, since malignancy diseases will provide similar
]. 99mTc-albumin, 99mTc-nanocolloid,
99mTctetrofosmin, FDG-PET, and 99mTc-MIBI are other sensitive
and non-specific radiopharmaceutical agents used for
diagnosis of infections including TB [
99mTc-HMPAO-WBC, 99mTc-HIg and peptide labeled are
specific process agents for infection/inflammation
imaging. However, these radiopharmaceuticals are basically not
specific to separate bacterial infection from sterile
inflammation. 99mTc-ciprofloxacin can be a more specific
radiopharmaceutical for bacterial infection imaging, because it is
taken up by living bacteria and it inactivates DNA gyrase [
]. Unfortunately 99mTc-ciprofloxacin cannot
differentiate TB from other bacterial infection, since ciprofloxacin
acts as a broad-spectrum antibiotic that can be taken up by
any living bacteria [
]. 99mTc-INH has been developed
to image TB, but clinically is not widely use [
Ethambutol is an active specific antibiotic against
mycobacterium. It inhibits mycolic acid in bacterial cell
]. Verma et al. showed that 99mTc-labeled
ethambutol is specifically taken up by Mycobacterium
tuberculosis, and can be image using gamma camera [
In vivo studies showed that the whole body bio-distribution
of 99mTc-ethambutol was consistent with the
pharmacokinetic characteristics of ethambutol as anti-tuberculosis drug
]. 99mTc-ethambutol remains in tubercular lesion as
it is bound to mycolic acid in the cell wall of bacteria, but
will be cleared out from non-tubercular lesions [
99mTc-ethambutol was not seen in dormant TB cases. The
advantages of 99mTc-ethambutol scintigraphy are it is a
noninvasive procedure and provides result faster than the
cytological test with minimal or no side effects [
The aim of this study was to evaluate the diagnostic value
of 99mTc-ethambutol scintigraphy in detecting and localizing
of TB infection.
Materials and methods
Retrospective cross-sectional study was done in the
Department of Nuclear Medicine and Molecular Imaging, Dr.
Hasan Sadikin General Hospital/Faculty of Medicine,
Universitas Padjadjaran Bandung, Indonesia. Secondary data
were collected from medical record. Subjects were patients
who were referred for 99mTc-ethambutol scintigraphy to
confirm or exclude TB infection from 2009 to 2015. The
duration between the start of ethambutol drug and the day of
99mTc-ethambutol scintigraphy test was recorded. Side effect
from injection of radiopharmaceuticals was observed.
Subjects without histopathological or microbiological data and
under TB treatment for more than 2 weeks were excluded
from this study. This study was approved by Health Research
Ethic Committee Faculty of Medicine Universitas
Padjadjaran no. 592/UN6.C1.3.2/KEPK/PN/2015.
Ethambutol cold kit was developed by Center for
Radioisotope and Radiopharmaceuticals Technology, National
Nuclear Energy Agency of Indonesian. Whole body and
SPECT/CT imaging in the suspected areas were done at 1
and 4 h following 370–740 MBq intravenous injection of
99mTc-ethambutol. SPECT/CT was done in the suspected
area of TB based on whole body imaging. Twenty-four hours
imaging was done if necessary. The results of
99mTc-ethambutol scintigraphy were compared with that of
histopathological or microbiological test.
99mTc‑ethambutol labeling of procedure
Ethambutol cold kit comes in 2 vials. One vial (A) contains
3.5 mg ethambutol and 5 mg mannitol. The other vial (B)
contains 400 µg SnCl2.2H2O and 2 mg sodium
pyrophosphate. One mL aquades was added to vial A and mixed well.
All the solution was taken from vial A and put into vial B
using sterilized fine syringe, and mixed well. 370–740 MBq
freshly eluted 99mTc was added to vial B. The mixture in vial
B was swirled and allowed to react for 5–10 min at room
temperature. Instant thin-layer chromatography (ITLC) was
performed for quality control using acetone as a solvent to
determine radiochemical purity of 99mTc-ethambutol. The
radiochemical purity should be more than 90% to be used in
this study. This based on the formulation for the
pre-determined radiochemical purity that 88–94% radiochemical
purity of 99mTc-ethambutol can be used [
There is no specific preparation for ethambutol scan.
Anterior and posterior whole body and SPECT/CT images were
done using a standard dual-head Gamma Camera SPECT/
CT (GE-Infinia®) with Low-Energy High-Resolution
(LEHR) Collimator at 1, 4 and if necessary 24 h
following intravenous injection of 99mTc-ethambutol. Injection
dose of 99mTc-ethambutol was 370–740 MBq. SPECT/CT
images were done covering lungs and other suspected area to
improve the sensitivity in detection of lesions. The subjects
were observed for any signs and symptoms from side effect
of radiopharmaceutical injection. Common side effects
include problems with vision, headaches, nausea, joint pain,
tiredness and allergic reaction.
The interpretation of image was based on the quality of
tracer uptake. Images were analyzed visually for qualitative
analysis. Normal distribution of 99mTc-ethambutol is seen
as high uptake in kidney, urinary bladder, liver and spleen.
There is no tracer uptake shown on bone, bone marrow,,
epiphysis, stomach and thyroid, soft tissue and lung as well.
Significant urinary activity was seen in 1 h, since the kidney
is the main excretory organ [
]. Any increased pathological
uptake of 99mTc-ethambutol seen in the area out of normal
distribution compared with that of the opposite area was
considered as positive results. The pathological uptake is
increasing gradually at 4- or 24-h images compared with that
of normal uptake. Negative result was considered if normal
radioactivity distribution was seen without any pathological
tracer uptake, or increased tracer uptake at 1 h, but
decreasing at 4 h image [
Statistic analysis was done to determine the sensitivity,
specificity, negative and positive predictive value as well
as accuracy by comparing the result of 99mTc-ethambutol
scintigraphy with that of histopathological or
microbiological using a 2 × 2 table.
One hundred and sixty-eight subjects out of 221 fulfilled the
inclusion and exclusion criteria. They were included in this
study. There were 110 (65.5%) males and 58 (34.5%) females
with mean age 34.52 ± 11.94 years and ranged 2–79 years
old. Fifty-three subjects with spondylitis TB were excluded
due to no data of histopathology or microbiological test.
Final diagnosis of pulmonary TB was 52 subjects,
lymphadenitis TB 33 subjects, spondylitis TB 40 subject, peritoneal
TB 20 subject and other extra-pulmonary TB 5 subjects.
Non-TB infection was found in 18 subjects. There were 23
subjects with history of taking ethambutol treatment less
than 2 weeks prior to ethambutol scintigraphy. The average
dose of 99mTc-ethambutol was 721.87 ± 95.09 MBq with
average percentage of labeling efficiency as 95.82± 0.86%
(Table 1). Normal whole body distribution of
99mTc-ethambutol at 1 and 4 h after injection of radiopharmaceutical is
shown in Fig. 1. Positive finding was seen on 1- and 4-h
whole body images (Fig. 2) and 4-h SPECT/CT images
(Fig. 3). Increase pathological tracer uptake was seen in the
upper lobe of the right lung. This finding was confirmed
as pulmonary TB by microbiological examination. Figure 4
shows a positive result of 99mTc-ethambutol scintigraphy in
subjects with final diagnosis of spondylitis TB with
There was concordance between 99mTc-ethambutol
scintigraphy results and mycobacterial or
histopathological finding in 156 of 168 subjects (92.9%). There were 131
(78%) subjects who were positive on both
99mTc-ethambutol scintigraphy and microbiological or histopathological
finding, while the other 25 (14.9%) subjects were negative
on both examinations. The results were discordant in 12
(7.1%) subjects. Five subjects were positive on
99mTc-ethambutol scintigraphy but negative on microbiological or
histopathological test. The other 7 subjects were negative
on 99mTc-ethambutol scintigraphy, but positive on
microbiological or histopathological test. All 23 subjects with
the history of taking ethambutol treatment showed
truepositive results. The duration time between the first day of
taking ethambutol drug and the day of 99mTc-ethambutol
scintigraphy test was 7–12 days.
Table 2 shows a 2 × 2 table between 99mTc-ethambutol
scintigraphy and histopathological/microbiological test
for pulmonary TB, extra-pulmonary TB and total subject.
Table 3 shows the sensitivity, specificity, positive
predictive value (PPV), negative predictive value (NPV) and
accuracy of 99mTc-ethambutol scintigraphy in the
diagnosis of pulmonary TB as 93.9, 85.7, 93.9, 85.7 and 91.4%,
respectively, for extra-pulmonary TB 95.5, 77.8, 97.9,
63.6, and 85.1%, respectively, and for total tuberculosis
94.9, 83.3, 96.3, 78.1 and 92.9%, respectively. There were
no signs and symptoms of the side effects observed after
the injection of radiopharmaceuticals.
In this study, we found that two-third of the subjects were
male with very wide range of age from 2 years to 79 years.
We excluded 53 subjects with clinical diagnosis of having
spondylitis TB. Histopathological or microbiological data
were not available because no specimen is available due to
the subject refusing to undergo surgery or tissue biopsy. The
radiochemical purity of 99mTc-ethambutol used in this study
was higher compared to that recommended by other study
based on the formulation [
Increased pathological uptake of 99mTc-ethambutol was
observed at focal lesion of active tuberculosis in1- and 4-h
images. This pathological uptake was due to increase and
retention of radiopharmaceuticals by live M.
tuberculosis. The retention of 99mTc-ethambutol in the 24-h image
increased the specificity and positive predictive value of
99mTc-ethambutol scintigraphy, particularly, in doubtful
cases. Any radiotracer uptake by infected/inflammation
lesions at the initial phase is nonspecific, since most of the
tracers are distributed at the blood pool lesion and
extracellular space [
]. This phenomenon is seen in
99mTc-ethambutol scintigraphy as well.
In this study, we found 92.9% subjects showed
concordance and 7.1% discordance between 99mTc-ethambutol
scintigraphy result and mycobacterial or
histopathological finding. The sensitivity and positive predictive value of
Fig. 4 99mTc-ethambutol SPECT/CT of patient with approved
spondylitis TB by histopathological examination. Specimen was taken
during surgery. CT images (left side) showed deformity of thoracic
spines with paravertebral abscess. 99mTc-ethambutol images (right
side) showed increased pathological tracer uptake at several thoracic
spines and surrounding paravertebral abscess
Table 2 2 × 2 table between 99mTc-ethambutol scintigraphy and
Histopathologic/microbiological test Total
Positive (n = 138) Negative (n = 30)
99mTc-ethambutol scintigraphy for the diagnosis of
pulmonary is more than 90% as well as for extra-pulmonary TB,
but the specificity and negative predictive values were less
than 90%. 99mTc-ciprofloxacin is more specific among other
radiopharmaceuticals for the diagnosis of bacterial
infection. Lee et al. showed that the sensitivity and specificity
of 99mTc-ciprofloxacin SPECT for detecting active
pulmonary tuberculosis before treatment were 80.0 and 90.9%,
respectively. The positive predictive value was 88.9% and
the negative predictive value was 83.3% [
]. We found that
the sensitivity, negative and positive predictive values of
99mTc-ethambutol scintigraphy were higher compared to that
in the study by Lee et al., but in the contrary, the specificity
was slightly lower. Theoretically, the specificity of
99mTcethambutol should be higher compared with that of
99mTcciprofloxacin, since 99mTc-ethambutol is more specific for
Mycobacterium tuberculosis. Low negative predictive value
in the diagnosis of TB could be due to a limited number of
subjects with non-TB. Negative TB was found in only 30
subjects, while positive TB was found in 138 subjects. Less
number of subjects with negative TB were found in
extrapulmonary TB compared with that for pulmonary TB. It is
recommended to do another study with comparable number
of subjects between positive and negative TB.
Tuberculosis lesions in human are very complex with a
wide range of pathological features. This variety of lesions
could be observed within a single individual patient
]. Due to their characteristic; these lesions
will provide either false-positive or false-negative results on
99mTc-ethambutol scintigraphy. False-positive result could
be caused by: (1) hypervascularization of non-specific
infection or inflammation [
], (2) difficulties to get the adequate
], (3) and at least 104 number of acid-fast
bacilli/mL of specimen culture are required to provide
positive result [
]. In this study, we found 5 false-positive
subjects: 3 subjects from the group of pulmonary TB and
the other 2 subjects from the group of extra-pulmonary TB
showed false-positive result. Hypervascularization could be
found in TB granuloma. High uptake of radioactivity seen
at solid lesions or nodules in lung parenchyma suggested
granuloma cellular uptakes just around the lesions of largely
filled cavities. Granuloma contains predominantly
intracellular M. tuberculosis with good vascularization which showed
high uptake of 99mTc-ethambutol. Negative smear sputum
microscopic test in those subjects could be because
granuloma did not contact with airway lung structure [
]. Subject with false positive on 99mTc-ethambutol
scintigraphy, but abnormal clinical feature and chest X-ray were
considered as suggestive for active pulmonary tuberculosis.
Those subjects were treated with anti-tuberculosis drugs. On
the follow-up, they showed better improve clinical features.
This false-positive case can be considered as true positive
based on good response following anti-tuberculosis
treatment, although smear sputum microscopic test was negative.
Performing serial late images could minimize false-positive
result of 99mTc-ethambutol scintigraphy due to
hypervascularization. Twenty-hour images following injection of
99mTcethambutol could be done if necessary.
In this study, we found false-negative results in 7 subjects,
3 subjects belong to pulmonary TB group and 4 subjects
belong to extra-pulmonary TB group. They showed negative
result on 99mTc-ethambutol scintigraphy, but positive on
microbiological or histopathological test. False-negative
result could be found in necrotic caseous lesions that spread
and destroy vasculature which lead to lack of
radiopharmaceutical supply from blood [
]. These necrotic lesions can
remain solid with very few bacilli. Necrotic caseous lesions
can be seen on X-ray without radiotracer uptake that caused
false negative results on 99mTc-ethambutol scintigraphy with
positive smear sputum microscopic test [
During the period of 5 years performing
99mTc-ethambutol scintigraphy, we found 13 negative 99mTc-ethambutol
scintigraphy results in patients suspected of having TB. All
of them were under intensive phase treatment using
ethambutol. Since the characteristic of 99mTc-ethambutol is similar
to ethambutol used for treatment, the question arises whether
negative result is true negative or false negative due to
competition between 99mTc-ethambutol as radiopharmaceutical
and ethambutol as anti-tuberculosis drug. In our study, 23
subjects with positive pulmonary TB based on smear
sputum microscopic test were positive on 99mTc-ethambutol
scintigraphy. All of these subjects showed positive result on
the second 99mTc-ethambutol scintigraphy performed after
taking ethambutol drug for 7–12 days. This finding showed
that taking drug during intensive treatment less than 2 weeks
would not affect the result of 99mTc-ethambutol scintigraphy.
In this study we did not find any sign and symptom related
to injection of 99mTc-ethambutol. Problem in vision due to
optic neuropathy or cardio-hepatotoxicity occurs very rarely
after several months of therapeutics. Ethambutol is freely
given to pediatric patients. Adverse effects of ethambutol are
rare and dose dependent. The diagnostic dose administered
is only less than 3.5 mg. In clinical context, it was
considered as a safe radiopharmaceutical, even in children [
This study showed that 99mTc-ethambutol scintigraphy is a
useful diagnostic imaging technique to detect and localize
both intra- and extra-pulmonary tuberculosis.
99mTc-ethambutol scintigraphy is safe to be performed even in pediatric
patient. Consuming ethambutol less than 2 weeks does not
influence the result of 99mTc-ethambutol scintigraphy.
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