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

b. 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 )
 BTA ( + ) = ditemukan kuman basil
Pemeriksaan hapus Dahak
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

2of
2. Radiologic
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
ed
oftota
(B)
the
of
(top)
disease
sextants
10
interest
Adjudicated
with
Waterfall
represent
heart)
lIn
after
responses
within
activity
A
are
separate
and
all
summary
with
treatment
respectively.
status
shown
panels,
2and
was
log
(ROIs)
of
thethorax
months
treatment
in
plot
all
subjects
log
evaluated
units
CT
6sum
tofeatures
atof
months
dark
encompassing
second-line
outcomes.
features.
top
(middle)
change
the
offrom
(C)
outcomes.
green
self-reporting
and
three
standardized
feature-by-feature
by
Waterfall
are
after
-100to
bottom
inFeatures
two
or
radiology
bars
Automated
displayed
automated
TB
discontinuing
6 separateradiologists
months(bottom)
visually
+200
Total
chemotherapy.
represent
plot
no
uptake
were
reader
of
Hounsfield
activity
showing
disease
extraction
identified
CT
change
changes
scored
value
subjects
TB
abnormal
semiquantitative
across
chemotherapy,
recurrence
baseline
(A)
in
(SUV).
units
per
disease
ofisPET
with
by
abnormal
presented
thethorax
sextant,
volumes
(HU).
delineating
total
extent
Baseline
confirmed
and
butCus-
activity
es-
and
with-
light
ex-
of
(ex-
and
in

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 from−100 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) Ren-
dering 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 out-
ward 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 recap-

are first removed to the level of the ribs, followed by removal of skeletal features to identify

CCT automated algorithm

CT Automated
T automated Algorithm
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 repre-
sented 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 abnor-
malities 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

PET (2 months) 0.96 (23/24)* 0.75 (3/4)*

Automated CT (6 months) 0.96 (23/24)* 0.75 (3/4)*
HU −100 to 200

Automated CT (2 months): 0.79 (19/24)* 0.75 (3/4)*

HU −100 to 200

Culture—solid (2 months) 0.79 (19/24) 0.5 (2/4)

Smear (2 months) 0.75 (18/24) 0.5 (2/4)

Culture—liquid (2 months) 0.58 (14/24) 0.5 (2/4)

*Estimates have been corrected for bias in selection of optimal threshold using cross-
validation
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)