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 Active TB 10% 有症狀有傳染性 Latent TB 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

乾酪化病灶 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

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 10 5 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

BACTERIOLOGY 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.

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 10-14 歲兒童 Group tested No. of person tested Reactors 檢查人數感染數 % 塗片培養均陽性 * 374 244 65.2 塗片陰性培養陽性 228 61 26.8 非開放性病人 221 39 17.7 無接觸對照組 709 157 22.1 *P<0.0001( 差異具統計學意義 ) 世界衛生組織資料 1976

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, sanda cara 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 Go bersdorf 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)

1882 抗酸性染色 Acid fast stain

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

乾酪化病灶 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

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 土壤微生物學 原理

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 初次治療常規用藥 First-line Anti-tuberculosis Drugs Isoniazid (INH) Rifampin (RMP) Pyrazinamide (PZA) Ethambutol (EMB)

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 70 60 50 40 30 20 10 MDR Any drug 0 Treatment failure Default Relapse New case * 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 * 如證實無 INH 或 RMP 抗藥, 則停用 EMB 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

Fixed Drug Combination Rifater (RFT) + EMB Rifater (each tab) = INH 80mg + RMP 120mg + PZA 250mg >=50kg 每日 5 錠體重每減 10kg 減 1 錠 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

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 TB 服藥入口 嚥下再走

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

* 依過去治療史分類 治療前評估 * TB Case 初治 過去治療史 N 新案 Y Return after default Relapse Failure Chronic case 再治 標準初次治療 照會專業醫師 Never treat multidurg-resistant TB (MDR-TB) without expert consultation WHO. Treatement of tuberculosis, 3 nd ed. 2003. WHO/CDS/TB 2003.313

Old WHO recommendations (before 2010) Regimen 4HREZ/2HR (Category I) Indications New cases 2SHREZ/1HREZ/5HRE (Category II) Retreatment cases Default Relapse after cure or completion

MDR-TB in Category I treatment failure 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% 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.

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