jurnal wahyu 2

Pembimbing :

dr. Suhermi Ismail SpRad

TUBERCULOSISPET/CT IMAGING CORRELATES WITH TREATMENT OUTCOME IN PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

Journal Reading

Dr. WahyudiPulmonologi dan Kedokteran Respirasi

TUBERCULOSIS

Penyakit yang disebabkan oleh infeksi

Mycobacterium tuberculosis complex

Pendahuluan

DIAGNOSIS TUBERCULOSIS1. 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 PENUNJANG2. 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 TUBERCULOSISOAT 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 perubahanDalam 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

. Radiologic responses to second-line TB chemotherapy. (A)2 and 6months, respectively. (C) Waterfall plot of change in PET total activityWaterfallplotofchangeinCTreaderscoresandcorrelationwithtreatmentand correlation with treatment outcomes. Total activity across thethorax (ex-outcomes. Adjudicated sum of three radiology reader semiquantitative es-cluding the heart) was evaluated by two separateradiologists by delineatingtimates of 10 separate CT features. Features were scored per sextant, andregions of interest (ROIs) encompassing visually identified disease and ex-summ ed sextants of all features are displayed showing baseline extent ofporting tota l activity in units of standardized uptake value (SUV). Baselinedisease (top) and logfold change after 2 months (middle) or 6 months(bottom)extent of disease and logfold changes are shown at top and bottom22of treatment. A summary of the feature-by-feature changes is presented in(2 months). In all panels, dark green bars represent subjects with confirmedfig. S1. (B) Waterfall plot of change in automated CT abnormal volumes andculture-negative status 6 months after discontinuing TB chemotherapy, lightcorrelation with treatment outcomes. Automated extraction of abnormalgreen bars represent subjects self-reporting no disease recurrence but with-lung density within thethorax from -100to +200 Hounsfield units (HU). Cus-

Fig. 1. Radiologic responses to second-line TB chemotherapy. (A)Waterfall plot of change in CT reader scores and correlation with treatmentoutcomes. Adjudicated sum of three radiology reader semiquantitative estimatesof 10 separate CT features. Features were scored per sextant, andsummed sextants of all features are displayed showing baseline extent ofdisease (top) and log2 fold change after 2months (middle) or 6months (bottom)of treatment. A summary of the feature-by-feature changes is presented infig. S1. (B) Waterfall plot of change in automated CT abnormal volumes andcorrelation with treatment outcomes. Automated extraction of abnormallung densitywithin the thorax from−100 to +200 Hounsfield units (HU). Customsoftware was used to extract all abnormal lung density data and computevolumes across various density ranges. Top panel shows baseline volumeof disease, and the middle and bottompanels show the log2 fold change at

2 and 6months, respectively. (C)Waterfall plot of change in PET total activityand correlation with treatment outcomes. Total activity across the thorax (excludingthe heart)was evaluated by two separate radiologists by delineatingregions of interest (ROIs) encompassing visually identified disease and exportingtotal activity in units of standardized uptake value (SUV). Baselineextent of disease and log2 fold changes are shown at top and bottom(2months). In all panels, dark green bars represent subjects with confirmedculture-negative status 6 months after discontinuing TB chemotherapy, lightgreen bars represent subjects self-reporting no disease recurrence but withoutconfirmatory cultures, and red bars represent patients with cultureconfirmeddisease recrudescence. Asterisk represents a patient who was initiallysuccessful on treatment but became noncompliant after 6months andsubsequently failed.

CT AUTOMATED LOGARITHM

Perubahan abnormal CT Volume ParuBln 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

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

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,

these regions are grown out toward the ribs using a second thresholding function to recap-

ture density in areas of extensive consolidation and collapse. (B) Flat rendered output ofdisease-associated voxels from one subject at study entry (top), 2 months (middle), and 6months (bottom) showing voxels from -500 to +100 HU.

CCT automated algorithmT automated algorithmCT 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 monthsof treatment.This scan shows a subject with right middle and lower lobe disease and no involvement ofthe left lung. In this representation, voxels between -100 and 200 HU are labeled gray (smoothed forclarity 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 rightmiddle 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 CONVERSIONCOMPARED TO CT AND PET SCAN CHANGES FOR PREDICTING TREATMENTOUTCOMES.

Modality Sensitivity Specificity

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

Automated CT (6 months)

HU −100 to 200

0.96 (23/24)* 0.75 (3/4)*

Automated CT (2 months):

HU −100 to 200

0.75 (3/4)*0.79 (19/24)*

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

• 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)

Kesimpulan