結核病的診斷與治療

高醫附設醫院 感染內科

盧柏樑 醫師

結核病~三千年歷史的古老疾病 埃及時代 西元前 3700-1000年

土偶 木乃伊 (Nesperhan, priest of Amun)

Primary TB

Latent TB

Active TB

10%

有症狀

有傳染性

Latent TB

90%

Active TB disease

• Latent TB infection progresses to active TB in

– 感染後馬上發病 (primary progression)

– 5%感染後兩年內發病

– 5%感染兩年以後發病

• 90% 終身Latent TB

• Risk greater if cell-mediated immunity impaired

結 核 病 的 診 斷

空洞

結核菌吸入肺內引起感染，當細菌繁殖，體內白血球開始與結核菌戰鬥，病灶痊癒，殘餘結核菌轉變成潛伏者，但並未死亡。當身體抵抗力下降，潛伏的結核菌又開始繁殖，甚至可能產生空洞。

乾酪化病灶

Chest Radiograph

• Abnormalities often seen in apical

or posterior segments of upper

lobe or superior segments of

lower lobe

• May have unusual appearance in

HIV-positive persons

• Cannot confirm diagnosis of TB

Arrow points to cavity in

patient's right upper lobe.

檢體採集

• Obtain 3 sputum specimens for smear examination and culture

• Persons unable to cough up sputum, induce

sputum, bronchoscopy or gastric aspiration

• Follow infection control precautions during

specimen collection

Smear Examination

• Strongly consider TB in patients with smears

containing acid-fast bacilli (AFB)

• Results should be available within 24 hours of

specimen collection

• Presumptive diagnosis of TB

AFB smear

AFB (shown in red) are tubercle bacilli

What Does AFB Smear Tells Us?

IF positive, it is TB or NTM (Non-TB

Mycobacterium) infection.

If negative, no infection or infection but less

than 105 AFB/ml in the specimen

50% culture-positive are Smear-negative

Still it is the Most Widely Used Test Worldwide

And has had a Great Role in TB Diagnosis

1.A minimum of 100,000 tubercle bacilli per

millilitre of sputum are necessary to be seen on

microscopy.

2.Apparently only a few hundred bacilli per millilitre

of sputum are sufficient to be detected by culture.

BACTERIOLOGY

分支桿菌培養

傳統培養方法(固態培養基)需時四至八週

比鏡檢更敏感, 可偵測到10-100隻細菌/ml

敏感度: 80-85 %, 特異性 98 %

部分痰抹片陰性病人仍可因培養陽性獲致確診

Cultures

• Use to confirm diagnosis of TB

• Culture all specimens, even if smear negative

• Results in 4 to 14 days when liquid medium

systems used

Colonies of M. tuberculosis growing on media

Different Culture Media

The Old Way

Egg-base. LJ, Ogawa, and Others

Agar-base. Middlebrook.

BACTEC 12B Radiometric

BACTEC 460 has become a “GOLD Standard”

for culture and Susceptibility testing

The New Way

Non-radiometric liquid culture systems

快速檢驗

• Molecular method

• PCR

– In house

– FDA approved

• Antigen detection

• 抗原鑑定

Latent TB infection

• Tuberculin skin test usually positive at 2-10

weeks

• Tubercle bacilli may remain dormant but viable

for many years

• No symptoms of active TB disease

• Not infectious

• Usually no progression in 90% of persons

Administering the Tuberculin Skin Test

• Inject intradermally 0.1 ml of 5

TU PPD tuberculin

• Produce wheal 6 mm to 10 mm

in diameter

• Do not recap, bend, or break

needles, or remove needles from syringes

• Follow universal precautions for infection control

Reading the Tuberculin Skin Test

• Read reaction 48-72 hours after injection

• Measure only induration

• Record reaction in millimeters

不同結核病患接觸者皮膚結核菌素測驗結果

塗片培養均陽性*

塗片陰性培養陽性

非開放性病人

無接觸對照組

Group

tested

374

228

221

709

感染數

244

61

39

157

No. of person tested

檢查人數

世界衛生組織資料 1976

%

65.2

26.8

17.7

22.1

Reactors

*P<0.0001（差異具統計學意義）

10-14歲兒童

抽血檢驗來偵測Latent infection

取代PPD test

• Interferon Gamma Release Assays

• ELISA to detect IFN-gamma

Important!!!

Choose a right method!

• Active infection

– Acid fast stain

– Culture

– Molecular

detection

• In house PCR

• Genprobe

• Latent infection

– Tuberculin skin

test

g interfetron assay

– ELISPOT

– T SPOT

Hypocrites (460-

370 BC) and the

Kos School

• tuberculosis, or consumption.

• A morbid process characterized by

progressive debilitation, coughing,

hemoptysis, and suppurating lung

lesions.

The answer for a cure is in Nature

• The main goal of the doctor treating

tuberculosis was to avoid hindering

natural cures.

• Continual rest, a balanced diet, and

abstaining from anything in excess

including sex were considered crucial.

休養, 均衡飲食與禁慾

• Bloodletting to drain contaminated blood

from the infected lung,

• thoracic poultices,

• “sandacara” pollen (from Cupressaceae

plants),

• drinking wine to induce coughing and

suppurating from lung lesions,

• thoracentesis preformed with a sharp

knife to drain fluid from the lung.

In 1860, Hermann Brehmer from Germany

started the first center in Gobersdorf

• to cure tuberculosis by rest. • The mountain fresh air and over-feeding in

an establishment more like a luxury hotel than a hospital would strengthen the patient.

• Villemin, 1865, established that the disease

was infectious.

– An Army Doctor.

– Young solider in Barracks got TB.

– Rabbit experiment

Collapsing the lung

• In 1888, an Italian, Carlo Forlanini

preformed the first intentional

spontaneous pneumothorax using a

needle to puncture the pleual cavity and

then administering nitrogen.

結核病的治療： 1944年開始化學藥物治療， 之前只能依賴療養。 (1930~ Collapse therapy)

抗酸性染色

Acid fast stain

1882

結核菌

學名:Mycobacterium tuberculosis

1882年科霍發現結核菌

耐酸菌(acid-fast bacilli)

細胞壁富於脂質而會妨害色素通過, 因而不易染色, 一旦染色不易被強酸脫色, 故又稱耐酸菌

分裂速度慢(1次/20hrs)

潮濕陰暗處可存活 6-8 個月, 陽光直接照射 4-6

小時死亡, 煮沸5分鐘可殺死

TB治療的歷史

• X-rays used in the 1920’s to scan the

lungs for TB.

– 診斷

– 追蹤療效

空洞

結核菌吸入肺內引起感染，當細菌繁殖，體內白血球開始與結核菌戰鬥，病灶痊癒，殘餘結核菌轉變成潛伏者，但並未死亡。當身體抵抗力下降，潛伏的結核菌又開始繁殖，甚至可能產生空洞。

乾酪化病灶

土壤微生物學原理

• 賽爾曼·A·瓦克斯曼

(Selman

Waksman )

• 因發現鏈黴素,

Streptomycin和其他抗生素而獲得1952年的諾貝爾獎

結核病治療的里程碑

SM 1944 開始

治療進步但產生抗藥性

BMJ 1948 2:p769-782

PAS 1943 開始

# PAS + SM 避免了SM 抗藥性

# 確立TB 化學治療原則：多種藥物合併治療

INAH in 1951開始

兩階段治療的觀念

INH+PAS+SM

INH+PAS

抗結核藥物

• First-line Anti-tuberculosis Drugs

– Isoniazid (INH)

– Rifampin (RMP)

– Pyrazinamide (PZA)

– Ethambutol (EMB)

初次治療常規用藥

PLOS Medicine 2007 e120

PLOS Medicine 2007 e120

PLOS Medicine 2007 e120

若藥物敏感性試驗INH為抗藥

可不可以用INH

第五版

區分為初治或再治病人

• 新病人 (New case)：不曾接受過抗結核藥治療或曾接受少於四週抗結核藥治療之病人。

• 再治病人(Retreatment case) – 復發 (Relapse)：曾接受一個完整療程之抗結核藥治療並經

醫師宣告治癒而再次痰塗片或培養陽性之病人。

– 失落再治 (Treatment after default)：中斷治療兩個月以上而再次痰塗片或培養陽性之病人。

– 失敗再治 (Treatment after failure)：治療五個月後依然痰塗片或培養陽性的病人，或者治療前痰陰性、治療二個月後變成痰塗片或培養陽性的病人。

疾病管制局: 結核病診治指引

Drug Resistance of MTB for each Treatment

Category in Taiwan

0

10

20

30

40

50

60

70

Treatment failure Default Relapse New case *

MDR Any drug

Chiang CY,et al. Formos Med Assoc, 2004.

* Jen-Jyh Lee et al, Tzu Chi Med J, 2003.

結核病初次治療 *

• 標準治療

– 2HRZE/4HRE

– 每日一次口服

– 前 2 個月 INH+RMP+PZA+EMB

– 後 4 個月 INH+RMP+EMB

* 適用初治新案 (new case)：不曾接受過抗結核藥治療或曾接受少於 4 週抗結核藥治療之病人。

如證實無 INH 或 RMP

抗藥, 則停用 EMB

•Rifater (each tab)

= INH 80mg

+ RMP 120mg

+ PZA 250mg

>=50kg 每日5錠

體重每減10kg 減1錠

Rifater (RFT) + EMB Rifinah (RFN) + EMB

•Rifinah300 (each tab)

= RMP 300mg + INH 150mg

•Rifinah150 (each tab)

= RMP 150mg + INH 100mg

>=50kg RFN300 每日2錠

<50kg RFN150 每日3錠

Fixed Drug Combination

若病人45kg, INH: 5*45=225, RIF: 10*45=450

3錠[RFN150] : INH 300, RIF 450

1錠[RFN150]+ 1錠[RFN300] : INH:250, RIF:450

也可 2.5錠INH 100*2.5=250, 3錠RIF 150*3=450

如果劑量過高, 容易副作用

若您是病人, 您會選哪種?

複方

• 病人接受度較高

• 沒有減少副作用, 甚至可能增加副作用

• 劑量上的困境

選高一點的劑量

有副作用再退回較低劑量

有助於減少抗藥性發生

指引

臨床指引的好處

• (1)增進品質並降低醫療錯誤

• (2)組織大量的資料

• (3)減少照護時的變數

• (4)排除浪費

• (5)改善對慢性病的處理

遵照指引, 病人就OK?

機器人醫生最遵守指引

送藥到手

服藥入口 嚥下再走

TB

同時四種藥 至少六個月

• 醫師, 假如吃結核病的藥有那麼多副作用， 您會願意吃嗎?

• 萬一有副作用，怎麼辦?

不能說白色謊言的年代

• 以往，醫師可以視情況”安撫病人”….?

• 現在，如果未說明藥物副作用是有錯的,

法官可依此判刑

• 現在, 開藥不符合指引也可能會為醫師引來災害

醫學是科學 也是藝術

• 醫護人員: 犯罪率最高?

• 臨床上, 以對病人最佳的方式幫助病人

– 不會百分百依照指引

治療效果評估

• 門診評估症狀及病人服藥順從性：

– 治療第1個月至少應回診2次，以後每月至少1次。

• 結核菌檢查

– 痰抹片耐酸菌鏡檢及結核菌培養：

• 每個月至少檢查1次，直到連續2個月培養陰性；

• 治療滿6個月時再檢查1次。

– 菌種鑑定：

• 每次培養陽性均應作菌種鑑定。

• 藥物敏感性試驗:

– 第1次培養陽性的菌株，

– 治療滿3個月後仍培養陽性的菌株。

疾病管制局: 結核病診治指引, 2006 第二版

治療效果評估 • 胸部X光檢查：

– 至少在治療滿2個月，及治療滿6個月時作胸部X光檢查。

-3

When to suspect MDR-TB?

Chavez AM, Blank R, Smith Fawzi MC, et al. Identifying early treatment failure on Category I therapy for pulmonary tuberculosis in Lima Ciudad, Peru. Int J Tuberc Lung Dis 2004; 8: 52-8.

Standards for Treatment

• Patients who have positive smears during the fifth month of treatment should be considered as treatment failures and have therapy modified appropriately.

• 治療第五個月仍痰陽性, 很可能治療失敗

• 需區分ＮＴＭ非結核分枝桿菌之可能性

治療前評估 *

Never treat multidurg-resistant TB

(MDR-TB) without expert consultation

TB Case

標準初次

治療 照會專業醫師

Y

N

過去治療史

新案

•Return after default

•Relapse

•Failure

•Chronic case

WHO. Treatement of tuberculosis, 3nd ed. 2003. WHO/CDS/TB 2003.313

* 依過去治療史分類

初治 再治

Old WHO recommendations (before 2010)

Regimen Indications

4HREZ/2HR

(Category I) New cases

2SHREZ/1HREZ/5HRE

(Category II)

Retreatment cases

• Default • Relapse after cure

or completion

MDR-TB in Category I treatment failure

1. Becerra MC et al. Int J Tuberc Lung Dis. 2000; 4(2): 108-14.

2. Fitzwater SP et al. Clin Inf Dis 2010; 51(4):371–37.

3. Quy HT et al. Int J Tuberc Lung Dis 2003; 7: 631-636.

4. Gler MT et al. Int J Tuberc Lung Dis 2011; 15: 652-656.

Study Country

Proportion of MDR-

TB in Category I

treatment failure

Becerra et al.1 Peru 94%

Fitzwater et al.2 Peru 100%

Quy et al.3 Vietnam 80%

Gler et al.4 Philippines 83%

所以不是每個人都治療6個月

肺外結核要治療更久

• 九個月

• 12個月

• 必要時 超過12個月……

完成治療

• 痰陰 (塗片及培養)

• 症狀改善

• 胸部X光改善

• 服藥期滿

謝謝 請指教

• 多種有效的抗結核藥物合併使用

• 藥物須按規服用

• 治療期間須夠長