Journal Reading

TUBERCULOSIS

PET/CT IMAGING CORRELATES WITH TREATMENT OUTCOME

IN PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

Pembimbing :
dr. Suhermi Ismail SpRad

Dr. Wahyudi
Pulmonologi dan Kedokteran Respirasi

Pendahuluan

TUBERCULOSIS

Penyakit yang disebabkan oleh infeksi

Mycobacterium tuberculosis complex

DIAGNOSIS TUBERCULOSIS
1.

Gejala klinik :

a.

gejala respiratorik : - batuk > 2 minggu

- batuk darah
- sesak napas
- nyeri dada

b.

Gejala sistemik : - Demam

- malaise keringat malam
- anoreksia dan penurunan berat badan

c.

Gejala tuberkulosis ekstra paru:

Pembesaran kelenjar getah bening ( lambat dan tidak nyeri )

PEMERIKSAAN PENUNJANG
2. Pemeriksaan Bakteriologik
a.

Pemeriksaan hapusan Dahak ( S P S )

Expertise : didapatkan Kuman BTA +

b.

Pemeriksaan Kultur kuman M.tuberculosis

. Eggs base media ( liquid culture )
. Agar base media ( solid culture )

Pemeriksaan hapus Dahak

BTA ( + ) = ditemukan kuman basil

tahan asam pada pemeriksaan
mikroskopiks

PEMERIKSAAN RADIOLOGIK

Foto toraks PA
CT scan toraks
PET Scan Toraks

Primary tuberculosis with lymphadenopathy in a 38-year-old woman. A: Chest

radiograph shows mediastinal widening in the right paratracheal region (arrows). B:
Computed tomography (CT) image (5-mm collimation) scan obtained at the level of the
great vessels shows enlarged bilateral paratracheal lymph nodes (arrows) with central
necrotic low attenuation and peripheral rim enhancement. C: CT image at the level of
the right hilum demonstrates enlarged lymph nodes in the subcarinal region (arrows)
and right hilum (arrowhead) with the same characteristics as those described in (B).

Pulmonary tuberculosis. A sputum positif case of pulmonary TB with clinically poor response to 2 months of tuberculous therapy.
Coronal plain CT (A) and PET/CT (B) with axial plain CT (C) and PET CT (D) images reveal extensive FDG-avid pulmonary
parenchymal lesions, the superior segment of the left lower lobe shows consolidation with central cavitation ( arrow) with an SUV
max of 10.1, these finding suggest active disease, indicating an inadequate response to therapy ( Indian J radiol Imaging, may
2008;18(2):141-147

PENGOBATAN TUBERCULOSIS
OAT yang dipakai
A) Jenis obat utama ( lini 1 ) yang digunakan :
. INH
. Rifampisin
. Pirazinamid
. Streptomisin
. Etambutol
B) Jenis obat tambahan lainnya ( lini 2 )
. Kanamisin
. Amikasin
. Kuinolon

PANDUAN OAT

TB Paru ( kasus baru ), BTA positif atau foto toraks, lesi luas
2 RHZE/4RH

TB Paru ( kasus kambuh & gagal pengobatan )

RHZES/1RHZE & 2RHZES/1RHZE/5RHE

TB Paru ( kasus Putus berobat )

2RHZES/1RHZE/5R3H3E3

 TB Paru BTA negatif lesi minimal

2 RHZE/4 R3H3

TB Paru Kronik
RHZES + obat lini 2 ( Min 18 bulan )

MDR TB
Sesuai uji resistensi + OAT lini 2 atau H seumur hidup

RESISTENSI GANDA /
MULTI DRUGS RESISTANCE
( MDR )

Mycobacterium Tuberculosis
resisten terhadap rifampisin
dan INH dengan atau tanpa OAT
lainnya.

PREVALENSI TB MDR DI INDONESIA

Indonesia berada diperingkat 8 dari 27 negara dengan
beban TB MDR terbanyak di dunia dengan perkiraan
pasien TB MDR
di indonesia sebesar 6900,
yaitu 1,9 darikasus baru dan
12 % dari kasus pengobatan ulang.
( WHO global report 2013 )

PENYEBAB TERJADINYA MDR

Pemakaian obat tunggal dalam pengobatan tuberkulosis

Penggunaan paduan obat yang tidak adekuat
Pemberian obat yang tidak teratur
Penggunaan obat kombinasi yang pencampuran yang tidak
dilakukan secara baik
Penyediaan obat yang tidak reguler
Pemakaian obat antituberculosis yang lama sehingga
menimbulkan kejenuhan

GAMBARAN
FOTO TORAKS DAN CT SCAN TORAKS

Korean J Radiol 10(3), June 2009

METODE PENELITIAN
RCT ( Ramdomized Clinical Trial )
Randomisasi, double-blind, placebo-controlled.( 2005-2012 )
Kriteria pasien :
- Pasien dewasa MDR TB yang medapatkan regimen pengobatan
MDR TB setidak tidaknya selama 18 bulan setelah konversi
kultur sputum( WHO guidelines)
- Pasien mendapatkan tambahan pengobatan yaitu metronidazole
500mg, 3x1/hari VS placebo selama fase initial ( 2 bln ), dipilih
secara acak.

- 35 subjek dengan MDR TB

11 subjek tidak melakukan PET/CT secara lengkap

( bln ke-2 dan Ke -6 )
Pada awal penelitian
>Kriteria inklusi : 1. usia ( median ) 37 thn
2. laki-laki ( 81%)
3. mempunyai penyakit berat 48%)
4. pada pemeriksaan foto toraks
ditemukan cavitas ( 52%)

- 24 Subjek mengikuti penelitian dari awal

hingga akhir

MATERIAL
A.CT reader study
.3 radiologis independent
.Memakai skor ( 0 - 4 )
.Subjek diakhir penelitian bagi atas kategori
1.

succsess : di bulan ke 6 setelah akhir pengobatan

secara klinis membaik dan kultur sputum bakteri
tuberculosis tidak tumbuh

2. Probable succsess : bila seseorang secara klinis membaik namun

tanpa konfirmasi mikrobiologik
3. failure : secara klinis dan mikrobiologik bertambah buruk

CT automated algorithm

menggunakan software algoritma terkomputerisasi untuk menilai volume paru

pada penyakit paru

 FDG
2-Deoxy-2-(18 F )-Fluoro-D-glucose
Digunakan sebagai penambahan ( bahan
kontras ) untuk CT resolusi tinggi, dilakukan
pada awal pengobatan dan bulan ke 2 setelah
pengobatan inisiasi

 PET Scan
Dilakukan hanya pada bulan ke 2 setelah pengobatan inisiasi

INTREPRETASI
Analisis densitas lesi
Pada radiodensitas ( - 500 sampai +300 HU)
> Densitas tinggi
kavitas dan konsolidasi dan fibrosis
> Densitas lebih rendah
lesi nodular

HASIL

CT reader study

Dilakukan pada awal, bln ke 2 dan ke 6, menggunakan CT-scan resolusi tinggi, oleh tiga
radiologist independent

10 gambaran CT , 3 menunjukkan perubahan

Dalam konsolidasi, kavitas ( P<0.05)
Bulan ke 2 AUC 0.92 ( 95% CI,0,79 to 1.0 )
Bulan Ke 6 AUC 0.93 ( 95% CI, 0.81 to 1.0)

CT READER STUDY

2o
2. fRadiologic
and
WaterfallplotofchangeinCTreaderscoresandcorrelationwithtreatment
outcomes.
cluding
timates
regions
summ
porting
disease
extent
fold
(2
fig.
culture-negative
correlation
green
lung
and
treatment.
months).
S1.
change
changes
correlation
density
6months,
bars
of
ed
tota
(B)
the
of(top)
disease
sextants
10
interest
Adjudicated
with
Waterfall
represent
heart)
lIn
after
responses
within
activity
Aare
separate
and
all
summary
with
treatment
respectively.
status
shown
2panels,
and
was
log
(ROIs)
of
thethorax
months
treatment
in
plot
all
subjects
log
evaluated
units
CT
6sum
tofeatures
atof
months
dark
encompassing
outcomes.
second-line
features.
top
(middle)
change
the
offrom
(C)
green
outcomes.
self-reporting
and
three
standardized
feature-by-feature
Waterfall
by
are
after
-100to
bottom
inFeatures
or
two
radiology
bars
Automated
displayed
automated
TB
discontinuing
6 separateradiologists
months(bottom)
visually
+200
Total
chemotherapy.
represent
plot
no
uptake
were
reader
of
activity
Hounsfield
showing
disease
extraction
identified
change
CT
changes
scored
value
subjects
TB
abnormal
semiquantitative
across
chemotherapy,
recurrence
baseline
(A)
in(SUV).
units
per
disease
of
isPET
with
by
presented
abnormal
thethorax
sextant,
volumes
(HU).
delineating
total
extent
Baseline
confirmed
and
butactivity
Cusesand
withlight
ex(exin
of
and

Fig. 1. Radiologic responses to second-line TB chemotherapy. (A)

Waterfall plot of change in CT reader scores and correlation with treatment
outcomes. Adjudicated sum of three radiology reader semiquantitative estimates
of 10 separate CT features. Features were scored per sextant, and
summed sextants of all features are displayed showing baseline extent of
disease (top) and log2 fold change after 2months (middle) or 6months (bottom)
of treatment. A summary of the feature-by-feature changes is presented in
fig. S1. (B) Waterfall plot of change in automated CT abnormal volumes and
correlation with treatment outcomes. Automated extraction of abnormal
lung densitywithin the thorax from100 to +200 Hounsfield units (HU). Custom
software was used to extract all abnormal lung density data and compute
volumes across various density ranges. Top panel shows baseline volume
of disease, and the middle and bottompanels show the log2 fold change at

2 and 6months, respectively. (C)Waterfall plot of change in PET total activity

and correlation with treatment outcomes. Total activity across the thorax (excluding
the heart)was evaluated by two separate radiologists by delineating
regions of interest (ROIs) encompassing visually identified disease and exporting
total activity in units of standardized uptake value (SUV). Baseline
extent of disease and log2 fold changes are shown at top and bottom
(2months). In all panels, dark green bars represent subjects with confirmed
culture-negative status 6 months after discontinuing TB chemotherapy, light
green bars represent subjects self-reporting no disease recurrence but without
confirmatory cultures, and red bars represent patients with cultureconfirmed
disease recrudescence. Asterisk represents a patient who was initially
successful on treatment but became noncompliant after 6months and
subsequently failed.

CT AUTOMATED LOGARITHM

Perubahan abnormal CT Volume Paru

Bln ke 2, AUC 0.80 (95% CI,0.59 to 1,0)
Bln ke 6 , AUC 0,97 ( 95% CI,0,91 to 1,0)
NOTE = CT reader Study dan CT automated logarithm bukan
untuk memperkirakan hasil pengobatan akhir

Fig. 3. Automated extraction of abnormal density associatedwith TB disease.(A) Rendering of intermediate steps in extracting lung voxels from CT scans. The outermost layers
the thorax region. The lung is then assigned by seeding from the carina and growing outward using thresholding to avoid mediastinal structures and lower hard organs. Finally,
ture density in areas of extensive consolidation and collapse. (B) Flat rendered output of
disease-associated voxels from one subject at study entry (top), 2 months (middle), and 6
months (bottom) showing voxels from -500 to +100 HU.
these regions are grown out toward the ribs using a second thresholding function to recapare first removed to the level of the ribs, followed by removal of skeletal features to identify

CCT automated algorithm

CT Automated
Algorithm
T automated
algorithm

PET Scan
PET scan dapat digunakan secara nyata untuk menunjukkan kelainan pada
beberapa paru paru subjek dengan cara pengambilan FDG, ( Bulan ke 2)

AUC 0.86 (95%,0.59 to 1.0)

Fig. 4. Heterogeneity of PET andCT responses in a singlesubject at study entry andafter2 months
of treatment.This scan shows a subject with right middle and lower lobe disease and no involvement of
the left lung. In this representation, voxels between -100 and 200 HU are labeled gray (smoothed for
clarity in the top views but unsmoothed from the primary data in the lower views). FDG uptake is represented by a red to yellow scale ranging from an SUV of 4 to 8. This subject had a collapse of the right
middle lobe and extensive abnormalities in the right lower lobe posteriorly. These parenchymal abnormalities resolved at the 2-month timepoint by CT and had minimal FDG uptake at 2 months, whereas the
collapse of the middle lobe retained FDG uptake and showed only minimal resolution.

TABLE : SENSITIVITY AND SPECIFICITY OF 2-MONTH SPUTUM

CULTURE CONVERSION
COMPARED TO CT AND PET SCAN CHANGES FOR PREDICTING
TREATMENT
OUTCOMES.
Modality

Sensitivity

Specificity

0.96 (23/24)*

0.75 (3/4)*

0.96 (23/24)*

0.75 (3/4)*

0.79 (19/24)*

0.75 (3/4)*

Culturesolid (2 months)

0.79 (19/24)

0.5 (2/4)

Smear (2 months)

0.75 (18/24)

0.5 (2/4)

Cultureliquid (2 months)

0.58 (14/24)

0.5 (2/4)

PET (2 months)
Automated CT (6 months)

HU 100 to 200
Automated CT (2 months):

HU 100 to 200

*Estimates have been corrected for bias in selection of optimal threshold using crossvalidation

Kesimpulan
Pada penelitian lainnya hapus dahak dan kultur dahak padat pada bulan ke 2 setidaknya efektif dalam
memperkirakan hasil dari pengobatan selanjutnya
Dalam perbandingan sensitivitas dengan modilitas radiologis PET pada bulan ke 2 dan CT pada bulan ke 6
lebih baik daripada kultur cair (eggs media )pada bulan ke 2 ( P=0.008 dan P=0.016).
PET pada bulan ke 2 dan CT bulan ke 6 tidak mempunyai perbedaan bermakna pada kultur padat ( Agar
media ) atau konversi pada hapus dahak pada bulan ke 2
Kelemahan penelitian ini adalah sampel penelitian yang kecil (n = 24 ) sehingga kurang memiliki Power
penelitian
> CT reader study

: Bulan ke 2 AUC 0.92 ( 95% CI,0,79 to 1.0 )

: Bulan Ke 6 AUC 0.93 ( 95% CI, 0.81 to 1.0

> CT Automated Logarithm : Bln ke 2, AUC 0.80 (95% CI,0.59 to 1,0)

Bln ke 6 , AUC 0,97 ( 95% CI,0,91 to 1,0)
> PET scan

: Bln Ke 2 AUC 0.86 (95%,0.59 to 1.0)