接觸者調查與預防性投藥 江振源. Director, Department of Lung Health and NCDs. 2011/04/29, National Taiwan University Hospital. Highlights of this presentation

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1 接觸者調查與預防性投藥 江振源 Director, Department of Lung Health and NCDs 2011/04/29, National Taiwan University Hospital Highlights of this presentation Contact examination in the context of National Tuberculosis Program Latent tuberculosis infection Tuberculin skin test Treatment of latent tuberculosis infection Feasibility, adherence, adverse effects Interferon-γ release assays Contact examination in Taiwan 1

2 Basis of current strategy of tuberculosis control To find, and render non-infectious, the infectious (smear positive) cases, which will reduce the risk of infection in the next generation; lead to a generation that is infection-free ; finally eliminate the disease. Current strategy will not be able to eliminate tuberculosis by Objectives of tuberculosis contact investigation Tuberculosis case finding To identify un-diagnosed source case To identify other prevalent cases Identification of persons infected with tuberculosis who are at risk of progression into active tuberculosis Intention to test Is intention to treat 2

3 Acquired resistance and transmission in tuberculosis Between Subject Transmission Latent TB Susceptible Latent TB, resistant Susceptible TB Resistant TB Inadequate treatment resulting in within subject acquired resistance Exposure Infection Patient delay Tuberculosis disease Health System delay Access care Inadequate treatment prolongs infectious duration Journey of TB patients Being identified as a suspect Being examined Being diagnosed Being treated Cured Recurrent The utility of contract investigation is context-dependent 3

4 Initial defaulter Defined as patients who were smear- positive on the laboratory register but who were not registered for anti-tuberculosis treatment 17% in Cape Town, South Africa, Int J Tuberc Lung Dis 2008; 12: % in Andhra Pradesh, India Int J Tuberc Lung Dis 2008; 12: Tuberculosis death without treatment Of the 536 culture positive tuberculosis patients notified in 2003 in Taipei, 29 (5.4%) were not treated 26 (89.7%) died, 2(6.9%) were re-notified one year later (3.5%) lost to follow-up. Overall, of the 536 tuberculosis patients, 97 (18.1%) died, in whom 26 (26.8%) died without anti-tuberculosis treatment. Chiang C-Y, et al. Int J Tuberc Lung Dis

5 Quality of sputum smear microscopy Patient and health system delays in the diagnosis and treatment of tuberculosis in Southern Taiwan Median patient delay was 7 days (range 0 730). Median health system delay was 23 days (range0 489), 13 for smear-positive patients and 37 for smear negative patients (P<0.005). Median total delay was 44 days (range 0 730). Chiang C-Y, et al. Int J Tuberc Lung Dis 2005:9:

6 Tuberculosis services in China Accessibility Patient delay 结核病人 Patients in the community Health system delay Completeness of reporting and Referral Quality of treatment of tuberculosis at township and county hospitals 村医 Village doctors 乡卫生院 Township health centers 县医院 County Hospitals 县结防所 County tuberculosis dispensary Analysis of care-seeking pathways of tuberculosis patients in Guangxi, China Logistic regression suggested that visiting county general hospitals tended to prolong patient diagnostic delay and cost more before TB diagnosis Wei X L, et al. Int J Tuberc Lung Dis 2009;13:

7 TB Suspects Mohanpur Upazila, Bangladesh % 35% 30% 25% 20% 15% 10% 5% 0% Number of suspects examined Proportion smear positive Data courtesy: Bangladesh NTP Latent tuberculosis infection a clinical status that infection with tuberculosis bacilli is established in a human host no clinical or bacteriological evidence of disease; may remain clinically unrecognized for a prolonged period of time and subsequently reactivate into clinical disease No fully protection against re-infection 7

8 Evidence of latent tuberculosis infection Pathological studies that recovered viable tuberculosis bacilli from subjects without tuberculosis. A PCR study done on normal lung tissues from Ethiopian and Mexican Individuals who had no tuberculosis lesions M. tuberculosis DNA is situated not only in macrophages but also type II pneumocytes, endothelial cells and fibroblast. No clinical tool that can directly identify tuberculous infection. Immunological response of host to mycobacterium detected by tuberculin skin test (Interferon-γ release assays) as a proxy of tuberculous infection Lancet 2000;356: Eur Respir J 2009;33:956- Tuberculin skin test a broth culture filtrate of tuberculosis bacilli first used by Robert Koch as a potential treatment of tuberculosis Purified protein derivative (PPD) prepared by Florence Seibert the international standard (PPD-S) recommended by WHO The most widely used tuberculin: PPD RT23 (Statens Serum Institut, Copenhagen, Denmark) Mantoux method: intradermal injection of PPD measurement of the transverse diameter of induration after hours 8

9 Distribution of reactors to 5 TU PPD among Alaskans tested in 1962 Reichman LB. Chest 1979; 76(suppl): The composite picture of TST The distribution among persons without any mycobacterial infection or with skin test anergy The distribution among persons with tuberculous infection The distribution among persons sensitized to mycobacteria other than tubercle bacilli who cross-react with tuberculin PPD Rieder HL. Tuber Lung Dis 1995; 76:

10 The composite picture of TST Rieder HL. Tuber Lung Dis 1995; 76: Percent with reac ction BCG vaccination on tuberculin reactivity Size of tuberculin reaction in mm Never BCG BCG in Infancy BCG in Pre-school BCG at older age Menzies R et al. Am Rev Respir Dis 1992;145:

11 Interpretation of Skin Test Reactions The appropriate criterion for defining a positive skin test t reaction depends d on the likelihood lih of tuberculosis infection and the risk of tuberculosis if infection has occurred. Am J Respir Crit Care Med 1994 Positive tuberculin skin test: a cut-off point that balances sensitivity against specificity. Eur Respir J 2005; 25: Global latent tuberculosis infection One-third of the world s population is latently infected with Mycobacterium tuberculosis. Estimated prevalence of latent TB infection Southeast Asia 46% Western Pacific 32% Africa 31% Eastern Mediterranean 27% Corbett EL, Arch Intern Med 2003; 163:

12 Selected risk factors for progression into disease, given infection HIV infection Time since infection Fibrotic lesions on chest radiograph Silicosis Carcinoma of head and neck Immunosuppresive therapy Underweight Diabetes Smoking Gastrectomy Excessive alcohol drinking Anti-TNF-alpha treatment Reduced progression into disease, given tuberculous infection Risk factor prevention and management Reduce prevalence of risk factors Reduce risk among subjects with risk factors Preventive therapy Post-exposure vaccine? 12

13 Selected controlled trials of INH preventive therapy Type of subjects No. Outcome Years of observation % reduction Household contacts to old cases, USA 2814 TB disease 4 54 Household contacts to new cases, USA TB disease Household contacts to new cases, Japan 2238 TB disease 1 30 Household contacts, Kenya 764 Positive bacteriology 3 80 Ferebee SH. Adv Tuberc Res 1970;17: Efficacy of various duration of isoniazid preventive therapy for tuberculosis Five-year follow-up in the IUAT trial No. of Cumulative 5-year Percentage Relative participants no. of cases incidence reduction risk Placebo wk wk wk Bull. WHO. 1982;60:

14 Five-year follow-up in the IUAT trial Benefit-to-risk ratio Cumulative no. of tuberculosis cases Cumulative no. of hepatitis Benefit-to-risk ratio prevented* cases incurred + 12 weeks weeks weeks * Reduction in cases over placebo regimen (per 1000 persons) + Excess of cases over placebo regimen (per 1000 persons) How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Comstock GW Int J Tuberc Lung Dis 1999; 3:

15 How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? 6 months of preventive treatment does not give optimal protection; ti More than 12 months of preventive treatment is not necessary; 9 10 months appears to be the optimal duration Comstock GW Int J Tuberc Lung Dis 1999; 3: Several randomized trials demonstrated that treatment of latent tuberculosis infection is efficacious in reducing the incidence of tuberculosis in HIV-infected TST-positive persons Cases of TB B6 alone INH + B6 PPD positive i No(%) Cases Incidence* RR for TB(95%CI) 6/25(24) ( ) 2/38(5) PPD negative No(%) Cases 5/35(14) 2/20(10) Incidence* RR for TB(95%CI) ( ) *per 100 person-years Pape JW. Lancet 1993;324:

16 A trial of three regimens to prevent tuberculosis in Ugandan HIV-infected adults The relative risk of tuberculosis as compared with placebo 6H 0.33 (95% CI 0.14 to 0.77); 3HR 0.40 (0.18 to 0.86); 3HRZ 051(024to108) 0.51 ( ). Whalen CC, et al. N Engl J Med 1997; 337: Preventive Therapy For HIV-infected Adults With No Previous History Of TB Meta-analysis of 10 placebo-controlled trials involving 8130 participants, adapted from Cochrane Database Syst Rev 2004; (1):CD Churchyard GJ, et al. JID 2007:196 (Suppl 1):s52-s62 16

17 Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults 6H vs 3RZ vs placebo The cumulative risk of tuberculosis in the first 2.5years was significantly lower in the H/RZ group than the placebo group (RR 0.55; 95% CI ) The effect of H/RZ diminished over time. Quigley MA. AIDS 2001, 15: Isoniazid preventive therapy, HAART and tuberculosis in HIV-infected adults, South Africa Golub JE, et al. AIDS 2009, 23:

18 Feasibility of Isoniazid Preventive Therapy (IPT) in Uganda Number Tested HIV-positive 9862 Returned to collect results 5594 Enrolled to IPT 1524 PPD tested 1344 PPD positive 579 No active TB after screening 520 Compliant with isoniazid for 6 months 323 Aisu et al. AIDS 1995; 9: 267 Adherence to Isoniazid Preventive Therapy (IPT) for HIV-positive patients, South Africa Of 229 HIV-positive clinic attendees, 94 (41.0%) were eligible for IPT 87 patients initiating IPT (6H) 41 (47.1%) completed IPT. Rowe KA, et al. Int J Tuberc Lung Dis 2005:9:

19 Bock NN, et al. Am J Respir Crit Cacr Med 1999;159: Isoniazid-related hepatitis Case Rate (/1000) < > 64 Age Group (yr) Probable Possible Kopanoff DE et al. Am Rev Respir Dis 1978;117:

20 Cumulative percentage of isoniazidrelated hepatitis, by month of occurrence 100 ses Cum mulative Percentage of Cas Month of Occurrence Probable (n=92) Possible (n=82) Kopanoff DE et al. Am Rev Respir Dis 1978;117: Death rate by year among persons started on INH preventive therapy Year No. of Deaths No. Started on Preventive Therapy Death Rate (/100,000) Total Snider DE et al. Am Rev Respir Dis 1992;145:

21 Adverse Event Data and Revised American Thoracic Society/CDC Recommendations Against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection United States, 2003 During October 2000 June 2003, CDC received reports of 48 patients 33 (69%) cases occurred in the second month of treatment. 11 (23%) patients died, 2 were HIV-infected Morb Mortal Wkly Rep 2003; 52: Contact screening and management: focus on children It is recommended that all National TB Programs screen household contacts for symptoms of disease offer isoniazid preventive therapy to children aged less than 5 years all HIV-infected children who are household contacts. WHO Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children

22 Incidence of tuberculosis among initial tuberculin reactors, by age when tuberculosis is diagnosed Comstock GW, et al. Am J Epidemiol 1974;99:131-8 Average age specific risk for disease development following primary tuberculous infection Age at primary Pulmonary TBM or miliary infection disease disease <1 year 30%-40% 10%-20% 1-2 years 10%-20% 2%-5% 2-5 years 5% 0.5% 6-10 years 2% <0.5% >10 years 10%-20% <0.5% Marais BJ, et al. Int J Tuberc Lung Dis 2004;8:

23 Diagnosis of Latent Tuberculosis Infection: Sensitivity TST Quanti-FERON-TB Gold In-Tube T-SPOT.TB Pai M, et al. Ann Intern Med 2008;149: Diagnosis of Latent Tuberculosis Infection: Specificity TST: non BCG-vaccinated QuantiFERON-TB Gold (BCG-vaccinated) TST: BCG-vaccinated T-SPOT.TB (Mainly BCG-vaccinated) Pai M, et al. Ann Intern Med 2008;149:

24 Positive predictive value for the risk of progression to tuberculosis Participants Follow-up QFT-GIT T-SPOT.TB TST 10mm Aichelburg 2009 HIV+ 19 months (median) 8.1% Diel 2011 Contacts 3.5 personyear 12.9% 48% 4.8% Kik 2010 Contacts 1.8 year 2.8% 3.3% 3.1% Leung 2010 Pneumoconiosis 30months 7.4% 6.4% (mean) Disease incidence and the number needed to treat to prevent one tuberculosis case within 5 years Leung CC, et al. ERJ Express 2010 Cumulative incidence in 5 years, % 24

25 歷年接觸者檢查結果 (%) ( 人 ) ( 患 者5 比率4 ) Source of data: 慢性病防治局 ( 年 ) ( 檢查人數) Active Case Finding of Tuberculosis in Taiwan, 1998 檢查人數新個案 新個案 (1/1000) 1/13981** (%) 巡檢 山地巡檢 安養精神院 監獄 接觸者 * 合計 * 接觸者為 85 年度之統計 ; **13981 為 86 年度之結核病報告總數 Source of data: 慢性病防治局 25

26 Taiwan CDC: 結核病接觸者檢查 於結核個案確診後 1 個月內, 完成結核病接觸者之基本資料調查及檢查痰塗片或痰培養陽性或胸部指標個案狀況 X 光有空洞 接觸者檢查時間 / 年齡 / 項目 確診 1 個月內 第 3 個月 第 12 個月 13 歲 ( 含 ) 以上完成 X-ray 痰塗片及培養皆陰性且胸部 X 光無空洞 單純肺外 未滿 13 歲完成 X-ray 及 TST 備註 : 僅需做一次 TST 備註 : 僅需做 X-ray 未滿 13 歲第一次 TST 陰性者, 三個月後應做第二次 TST 13 歲 ( 含 ) 以上再次完成第二次 X-ray 未滿 13 歲再次完成第二次 X-ray ㄨㄨ ㄨㄨ 備註 : 第二次 TST 陰性及指標個案確診即已按規服藥, 則此次不需做 X-ray -ray ㄨ備註 : 第 1 次 TST 陽性及胸部 X 光正常者, 則此次需再做 X * 指標個案被通報為多重抗藥性肺結核 (MDRTB) 個案 : 自被通報 MDRTB 日一個月內, 其接觸者應再次完成胸部 X 光檢查, 日後每隔半年進行乙次追蹤檢查, 且持續追蹤 2 年 * 指標個案為慢性傳染性肺結核個案 : 其接觸者每年應進行追蹤胸部 X 光檢查 * 接觸者如為孕婦, 若可取得痰檢體, 應先行查痰, 如有咳嗽症狀者, 由臨床醫師視情況決定是否安排胸部 X 光檢查 備註 : 一 上揭表格內容說明 : : 代表須執行, ㄨ代表不須執行, 惟備註為特殊情況務必注意 二 所有接觸者均進行胸部 X 光檢查, 惟半年內曾照胸部 X 光, 並能提出正常證明者, 可不必再做第一次檢查, 但如出現疑似異常症狀, 仍需隨時進行檢查 ㄨ Current approach in Contact examination of Taiwan CDC 13 year-old : tuberculosis case finding: prevalent and incident cases < 13 year-old : tuberculosis case finding: prevalent and incident cases Isoniazid preventive therapy What is the likely magnitude of impact on the epidemic of tuberculosis in Taiwan? reducing the risk of transmission reducing the risk of progression into active tuberculosis 26

27 衛生署疾病管制局結核病十年減半全民動員第一期計畫執行成果報告, 2011 衛生署疾病管制局結核病十年減半全民動員第一期計畫執行成果報告,

28 結核病年齡別發生率 衛生署疾病管制局結核病十年減半全民動員第一期計畫執行成果報告, 2011 TB rate of contact (first year) and Taiwan TB incidence,2005 Ling DL et al, Contact Investigation of Tuberculosis in Taiwan (2009 胸腔暨重症醫學年會 oral presentation) 28

29 Ling DL et al, Contact Investigation of Tuberculosis in Taiwan (2009 胸腔暨重症醫學年會 oral presentation) TB rate during the 3 year follow-up (n=33,596) LTBI 治療對於 <13 歲兒童接觸者之效益 2010 臺灣胸腔科年會口頭報 Courtesy of data: Taiwan CDC 29

30 In summary Contact examination contributes to tuberculosis case finding in most settings Careful evaluation to exclude active TB is essential in the treatment of latent tuberculous infection Treatment of latent TB infection is efficacious as individual intervention but its effectiveness as a measure of population TB control varies Adherence to treatment of latent tuberculosis treatment is crucial The utility of Interferon-γ release assays in predicting progression to disease is not impressive 30