結核病合併糖尿病個案 診療與照護 103年結核病個案管理專員教育初階訓練

主題大綱 Pathogenesis of DM and TB Colliding epidemics of DM & TB Bi-directional screening of DM & TB Co-management of DM-TB patients

糖尿病：疾病機轉與長期併發症

糖尿病的診斷 2009年起，ADA新增為診斷的標準 前三項診斷，可能需要repeated testing以確定診斷

Pathogenesis of TB Proposed mechanism of HIV-induced reactivation of latent TB. (Stage 1) Necrotic granuloma functioning “normally” in an individual with latent TB. (Stage 2) HIV enters the granuloma and induces functional changes within T cells and macrophages. HIV also kills activated T cells. (Stage 3) The decrease in T cell number and increase in cellular dysfunction lead to a functional disruption of the granuloma. This may lead to increased dissemination. (Stage 4a) Granulomas functionally disrupted shortly after HIV infection leads to continued M. tuberculosis dissemination and early TB reactivation. (Stage 4b) Fibrotic granulomas temporarily reestablish granuloma containment, which prevents reactivation. Diedrich C R , and Flynn J L Infect. Immun. 2011;79:1407-1417

糖尿病病人對於結核菌的免疫機轉 動物實驗: 糖尿病造成的併發症對免疫的影響仍待研究: 糖尿病老鼠受到結核菌感染時，相較於非糖尿病老鼠有較高的細菌量 罹患糖尿病的老鼠體內有較低的 IFN-Ƴ, IL-12，以及對於結核菌專一抗原(ESAT-6)反應的T細胞數目較低 此外嗜中性球對於細菌毒殺的能力較差 糖尿病造成的併發症對免疫的影響仍待研究: 肺部微小血管病變 腎功能衰退 Journal of immunology. 2010;184(11):6275-82. Clinical Microbiology. 2008;27(2):97-103. Diabetic medicine 1997;14(1):29-34. The American journal of medicine. 1982;72(3):439-50

Colliding epidemics of TB and DM 全球的糖尿病流行病學: Prevalent case: 382 million impaired glucose intolerance: 316 million 預估至2035年，糖尿病個案會增至 592 million 估計有46%的個案未被診斷 亞洲: 印度和中國是糖尿病人最多的國家；同時也是結核病高負擔國家之一; 接下來是Brazil, Bangladesh, Indonesia, Pakistan, Russia involving 199 countries and 2.7 million persons Estimates based on population growth, aging and urbanization cardiovascular disease diabetes mellitus (DM) cancer chronic obstructive pulmonary disease Predicted to be the cause of over 75% of global deaths by 2030 In parts of rural South Africa, there is already an epidemiological transition A national survey in China: Involving over representative 46, 000 adults between 2007 and 2008 estimated 92 million adults had DM when extrapolated to the total population, much more than a previous estimation of approximately 42 million A hospital-based study in China: more than half of persons with known DM experience chronic complications and exhibit poor glucose control International Diabetes Federation. IDF diabetes atlas. 6th ed.

Global burden of diabetes

http://www.idf.org/diabetesatlas/5e/diabetes-and-tuberculosis

DM Increases the Risk of Active TB 在不同的流行病學研究可觀察到糖尿病會增加結核病的發病風險，而世代研究的統合分析發現相較於糖尿病發生結核病的風險，是沒有糖尿病的族群的3倍 PLoS Med 20095(7): e152.

血糖控制與結核病發病風險 Animal study: Hyperglycemia and vulnerability to TB levels of IFN-Ƴ were negatively correlated with levels of HbA1c Hyperglycemia and vulnerability to TB A cohort study form Hong Kong hemoglobin A1c ≥7% (vs. <7%), with adjusted hazard ratios of 3.11 (95% CI: 1.63, 5.92) Severity of DM: higher risk of developing active TB in insulin-dependent DM patients than NIDDM Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed with baseline hemoglobin A1c ≥7% (vs. <7%), with adjusted hazard ratios of 3.11 (95% confidence interval: 1.63, 5.92), 3.08 (95% confidence interval: 1.44, 6.57), 3.63 (95% confidence interval: 1.79, 7.33), and 0.77 (95% confidence interval: 0.18, 3.35), respectively Kekkaku 72: 617–622. Am J Epidemiol 2008;167:1486–1494 Rev Med Chil 1989; 117:979-83 Trop Doct 1990; 20: 147-50

Source: “Global epidemiology of tuberculosis: prospects for control,”Seminars in Respiratory and Critical Care Medicine, vol. 29, no. 5, pp. 481–491, 2008.

http://www.idf.org/diabetesatlas/5e/diabetes-and-tuberculosis

台灣糖尿病流行病學 1999-2004年的健保資料庫分析: 台灣的成年人糖尿病盛行率由1999年4.8%  2004年6.8% 20-40歲的盛行率增加趨勢比40歲以上明顯 女性的盛行率雖然較男性高，但男性的糖尿病發生率逐年升高 糖尿病臨床照護指引2012: 中華民國糖尿病學會

用健保資料庫分析2000-2009 DM epi in Tw, DM definition: >= 3 outpatient clinic or 1 inpatient ICD-9-CM of 250

DM and TB risk in Taiwan 一般糖尿病病人(aHR=2.09,1.10–3.95)和已接受治療的糖尿病病人(aHR=2.60,1.34–5.03)，相對於沒有糖尿病者，均有較高的結核病發病風險 隨著糖尿病的併發症越多，嚴重度越高，結核病發病風險隨之增加 2000-2004 study population : 9% were classified as having DM and 7% had treated DM. The median age was 37.91 years CID 2012; 54(6):818–25

DM-TB in Taiwan (2) 依據結核病通報與健保資料庫勾稽，22.6％的結核病人符合糖尿病診斷碼 合併糖尿病的結核病人，與結核病12個月的死亡相關 Asia Pac J Public Health. 2011 Dec 23

Clinical manifestation of TB among DM patients More atypical lesions? More severity of TB disease? 沒有一致的定論

糖尿病合併結核病，其結核病治療預後 延遲細菌學陰轉 結核病治療期間的死亡 2-3 month culture conversion: relative risks ranged from 0.79 to 3.25 Time to culture conversion: 比非糖尿病患者延遲 結核病治療期間的死亡 Treatment failure and death: 1.7 times adjusted for age and other potential confounders, finding a pooled odds ratio of 4.95 (95% CI: 2.69 to 9.10) Baker et al. BMC Medicine 2011, 9:81

DM & TB relapse SR & MA: pooled RR: 3.89 (95% CI: 2.43 to 6.23) from 5 observational studies The presence of DM during previous anti-TB treatment was independently associated with subsequent TB recurrence in Taiwan (adjusted OR =1.96, 95% CI: 1.22-3.15) HA1C: proxy of diabetic care DM-TB without any A1C during TB treatment had higher risk of TB relapse (aOR: 1.98, 1.13-3.45) than at least once A1C (aOR: 1.62, 0.8-3.29) and those without DM Baker et al. BMC Medicine 2011, 9:81 Lee et al. Plos one March 2014 | Volume 9 | Issue 3 | e92623

Collaborative framework for care and control of TB and DM 基於過去HIV/TB的共同照護經驗，來建立DM/TB的共同照護架構 整合照護資源 Operational studies conducted in China and India avoid unnecessary duplication of service delivery structures promote optimal and well-coordinated use of scarce health-care resources builds on the experience of TB/HIV collaboration, and applies its key elements to TB and diabetes the framework is provisional in nature, with existing evidence from observational studies being used to support policy recommendations

Detect and manage TB in DM patients 對於糖尿病病人，建議在結核病的背景盛行率達到100/100,000 以上時，應進行結核病的篩檢 當糖尿病病人規則回診追蹤時，若詢問病人出現兩週以上的慢性咳嗽，要懷疑可能是結核病 懷疑糖尿病病人可能為結核病的疑似個案，應盡快轉介病人進行結核病的診斷與治療 台灣糖尿病臨床照護指引2012: 當糖尿病人咳嗽超過兩週時，建議轉診至胸腔科或感染科，進一步篩檢結核菌感染 糖尿病的門診或醫療照護機構，應有院內感染控制計畫，包含如何早期診斷結核病以及環境控制，以減少一旦出現傳染性病人所造成院內傳播的風險 WHO: Collaborative framework for care and control of TB and DM

Detect and manage DM in patients with TB 結核病診治指引第五版:結核病人應在開始抗結核藥物治療時篩檢糖尿病 篩檢工具可包含fasting blood glucose, random blood glucose or HbA1C 在開始結核病治療的初期(如: 開始治療的四週)，對於一開始血糖偏高的病人進行反覆的血糖檢測，會有助於確定糖尿病診斷，並及早開始控制血糖 第一線照護結核病的機構和工作人員，需要有血糖機並熟悉如何使用 ease of use, cheapness, speed, reliability and acceptability are paramount. This method will regularly identify more diabetes patients than fasting and/or random blood sugar (FBS/RBS) WHO: Collaborative framework for care and control of TB and DM

建議篩檢流程 可以使用的資源: 全民健康保險成人預防保健服務 40歲以上民眾，每 3 年篩檢 1 次；65歲以上民眾，每年篩檢 1 次 A postprandial blood glucose measurement with a glucometer 2 hours after a meal is the preferred method fasting and/or random blood sugar(FBS/RBS): sensitivity is lower than for postprandial blood glucose HbA1c or the oral glucose tolerance test is effective but expensive and time-consuming 可以使用的資源: 全民健康保險成人預防保健服務 40歲以上民眾，每 3 年篩檢 1 次；65歲以上民眾，每年篩檢 1 次 2013年糖尿病整合指引綱要: 中華民國糖尿病學會

糖尿病合併結核病: 藥物交互作用及血糖監測 Rifampicin (rifampin)是強力的CYP450酵素促進劑 導致口服降血糖藥物，如: Sulfonylureas/TZD的濃度下降而影響血糖控制 因此在結核病治療期間仍需監測血糖 可考慮TB治療前四週每週監測，當血糖控制穩定可減少監測頻率，但仍建議每月監測血糖 TB個案管理定期訪視和都治關懷員協助病人自我監測血糖 轉介糖尿病照護網尋求專業協助 USAPI Standards for the Management of Tuberculosis and Diabetes http://www.currytbcenter.ucsf.edu/international/tbdm_poster_pressquality.pdf

Serum concentration ↓22-39% AUC↓24-57% Serum concentration ↓54-55%

糖尿病人之治療目標 非重症住院病人建議 空腹血糖<140 mg/dl 隨機血糖<180 mg/dl 2013年糖尿病整合指引綱要: 中華民國糖尿病學會

合併糖尿病之結核病治療 IUATLD & WHO: 美國: 尚無定論: 目前對於合併糖尿病的結核病治療建議，和對一般TB病人並無差異 建議對於合併糖尿病，診斷結核病時合併有開洞病灶，且治療二個月仍培養陽性，建議延長continuation phase,治療為九個月 尚無定論: monitoring of drug levels and dose adjustment and/or a longer regimen (i.e., longer intensive or continuation phase)? 在印尼的研究曾發現，DM病人使用RMP其血中濃度低於非DM病人 DM本身就可能影響口服藥物的吸收，減少血中和藥物binding的蛋白質濃度，以及合併腎功能不全等 可能造成TB藥物在血中濃度的下降 Virginia會針對TB　treatment non-response的病人去測血中的藥物濃度來考慮ＴＢ藥物劑量調整 WHO: Guidelines for treatment of tuberculosis, fourth edition ATS, CDC, IDSA: Treatment of Tuberculosis. MMWR June 20, 2003 / 52(RR11);1-77

初次治療時程的延長 結核病診治指引 第五版 初次治療的病人如果在治療滿2個月時痰培養仍然陽性，要特別加強查痰，密切注意是否已在治療中變成抗藥。發現這類病情改善不如預期的情形，除了排除抗藥、或服藥順從性不佳的問題外，可考慮延長4.1 (INH + RMP + PZA + EMB 2個月+ INH + RMP + EMB 4個月)的建議處方3到6個月。 治療免疫力不好（如糖尿病、腎功能不全、接受抑制免疫力藥物治療等等）、胸部Ⅹ光病灶嚴重、或痰陰轉較慢的病人，主治醫師可依據病人的臨床狀況，考慮延長治療的時間。 初次治療的病人，如果合併HIV 感染，請一律延長4.1的建議處方3個月。 結核病診治指引(第五版): 第四章結核病的治療 http://www.cdc.gov.tw/professional/info.aspx?treeid=BEAC9C103DF952C4&nowtreeid=6744C19C09435458&tid=E36C98D85972C6AA

DM-TB的照護 給予Vit. B6 (10 – 25 mg/day)預防INH引起的周邊神經病變 需要依照腎功能(Ccr<30)調整Pyrazinamide及ethambutol的頻率 確定合併糖尿病的TB病人，對於TB的治療反應 是否治療失敗/抗藥性/確定病人可達”治癒” 由於DM-TB病人有較高的TB復發風險，完治後仍應衛教TB相關症狀/回診追蹤 TB完治後，仍要注意血糖控制!! USAPI Standards for the Management of Tuberculosis and Diabetes http://www.currytbcenter.ucsf.edu/international/tbdm_poster_pressquality.pdf

都治對於DM-TB病人的角色 都治確保服藥順從性 (包含結核病用藥與降血糖藥物) 協助病人self monitoring of glucose control, 特別是使用胰島素控制血糖的病人 HbA1c在血糖控制尚未達到目標，應三個月監測一次;若血糖控制穩定，則一年至少檢測兩次 協助副作用的觀察: 特別是低血糖 Patient support/Diabetes self management education/life style change

糖尿病人臨床監測建議表

Index: Key Messages for TB and Diabetes

總結：公衛及醫療端個案管理師之工作內容 *失敗：治療第五個月及以後依然S(+)或C(+)，