1. Non-tuberculous mycobacteria (NTM) lung disease Yee Hyung Kim - As a Emerging Infectious Disease -

2. Classification of Mycobacterial Species Mycobacteria M. leprae M. TB Complex Nontuberculous mycobacteria (NTM) = atypical mycobacteria = mycobacteria other than TB (MOTT) M.tuberculosis M.africanum M.bovis M.microti M.avium complex (MAC) M.avium M.intracellulare M.kansasii, M.abscessus M.fortuitum, M.malmoense, M.xenopi M.szulgai, M.chelonae ……

3. > 125 NTM species have been cataloged in 2007 Am J Respir Crit Care Med 2007, 175, 367 Too many NTM species www.BACTERIO.cict.fr/m/mycobacteriul.html : A complete list of all recognized NTM species minute differences in the 16S rRNA gene

4. Human Disease due to NTM Pulmonary disease (90%) Slow growing mycobacteria (SGM) MAC (M.avium/intracellulare complex) M. kansasii, M. malmoense M. szulgai, M. xenopi Rapig growing mycobacteria (RGM) M. abscessus, M. fortuitum Lymphadenitis Localized skin, soft tissue and skeletal infection Disseminated disease

5. Comparison with M.TB Normal inhabitants of the environment (tap water, soil) –Ubiquitous Not an obligate human pathogen –Either pathogen or colonizer/contaminants No person-to-person transmission –Isolation is not necessary to prevent disease spread Not cause reactivation disease

6. Annual isolation prevalence of pulmonary NTM in Ontario Thorax 2007; 62; 661

7. Annual NTM frequencies of the patients in KOREA Korean Institute of Tuberculosis, 2008

8. Total frequency of isolated NTM Korean Institute of Tuberculosis, 2008 17,915 isolates from 10,242 patients (1993 ~ 2006) N=11,705 (65%) N=2,076 (11.59%) N=762 (4.25%) N=1,279 (7.14%)

9. Clinical significance of NTM isolated from respiratory specimens in Korea NTM-positive culture of 1,548 respiratory specimen from 794 pts –131 patients (17%) : Definite NTM lung disease –64 patients (8%) : Probable NTM lung disease –Others (599 pts, 75%) : Unlikely disease Chest 2006;129:341

10. Clinical significance of pulmonary NTM isolates, Ontario, CANADA 2,090 patients with pulmonary NTM isolates in 2003 1997 ATS Diagnostic criteria for NTM 119 pts with adequate information for all ATS criteria 33% (39/119) fulfilled all criteria : NTM lung disease Thorax 2007; 62; 661

11. Etiology of NTM lung disease Case series in KOREA Bai et alLew et alKoh et alLee et al Study period 1980-19901982-1991 2001.10 - 2002.3 2002.1 - 2002.12 No of patients 59294272 M. avium complex 29 (49%)19 (66%)23 (55%)40 (56%) M. intracellulare 1822 M. avium 518 M. abscessus 10 (17%)4 (14%)12 (28%)15 (21%) M. fortuitum 12 (20%)5 (17%)4 (10%)11 (15%) M. kansasii --2 (5%)2 (3%) Miscellaneous 8 (14%)1 (3%)1 (2%)4 (5%) J Korean Med Sci 2005, 20, 913

12. Sputum AFB smear/culture Mycobacteria = M. tuberculosis + NTM Carbol-fuchsin stain (Ziehl-Neelsen methods) Solid Media 3 to 8 weeks

13. AFB 도말 혹은 배양 양성이면 이 결과는 결핵일까 ? NTM 일까 ?

14. Examples of Report “Mycobacterium species isolated” “AFB isolated” “Growth for AFB” “AFB Culture” M.TB 라는 말은 없다 !!!....TB vs NTM ??

15. Recovery rate of NTM from AFB smear-positive sputum specimens Reference Proportion of M. TB and NTM in AFB smear-positive sputum CountrySpecimen (n)M.TB (n, %)NTM (n, %) Levy et al (1989)South Africa249249 (100)0 (0) Coll et al (2003)Spain185146 (79)39 (21) Lipsky et al (1984)USA5857 (98)1 (2) Gordin et al (1990)USA142137 (96)5 (4) Yajko et al (1994)USA306273 (89)33 (11) Stone et al (1997)USA387291 (75)96 (25) Wright et al (1998)USA1315677 (51)638 (49) SMC (1999~2001)South Korea13281207 (91)121 (9) Int J Tuberc Lung Dis, 2005, 9(9), 1046

16. Prevalence of NTM lung disease in patient with AFB smear-positive specimens by Age Int J Tuberc Lung Dis, 2006; 10(9); 1001

17. Algorithm Suspected Pulmonary TB in U.S. AFB smear (+) TB-PCR (+) AFB smear (+) TB-PCR (-) AFB smear (-) TB-PCR (+) AFB smear (-) TB-PCR (-) Presumed to have M. TB Test for inhibitor Clinical Judgment No inhibitor Additional test AFB smear (+) TB-PCR (-) No inhibitor Inhibitor present 3 sputum AFB smear & culture TB-PCR on 1st sputum, 1st smear-positive sputum Additional test for TB-PCR Additional TB-PCR (+) Presumed to have M. TB Presumed to have NTM CDC. MMWR 2000;49:593

18. HospitalStudy PeriodAllNTM Park et al. 세브란스병원 1990.12 - 1991. 5 726 112 (15.4%) Nah et al. 서울아산병원 1992. 2 - 1993. 8 1993. 9 - 1995. 3 1995. 4 - 1995. 8 NA 13% 24% 33% Lee et al. 서울아산병원 1999. 1 - 1999.122,228 489 (21.9%) Lee et al. 전남대학병원 1999. 4 - 1999. 6 128 22 (17.2%) Koh et al. 삼성서울병원 1997. 7 - 2001.124,1691,273 (30.5%) Tuberc Respir Dis, 2003;54:22 Recovery rate of NTM from AFB culture- positive sputum specimens in KOREA

19. AFB 도말 / 배양 해석의 개념이 바뀌어야 한다 ! Increasing NTM frequencies of the patients Korean Institute of Tuberculosis, 2008

20. Methods for Identification of Mycobacteria from Culture Morphology –rough, nonpigmented, corded colonies Biochemical test (Conventional test) –positive niacin test –weak catalase activity that is lost completely by heating to 68  C –positive nitrate reduction test Nucleic acid hybridization High performance liquid chromatography (HPLC) Nucleic acid sequencing

21. AFB 배양 결과 및 균 동정 보고의 사례 (I) 검체정보검사명검사결과상태소견 [ 항산균검사 ] 검체명 : Sputum 상태 : 최종보고 접수일 :08/07/07 보고일 : 08/08/08 AFB stain/ culture 최종 보고 M.tuberculosis complex Ag test (-) AFB stain No Acid Fast Bacilli 최종 보고 Culture 1+ (4 개의 집락 ) 최종 보고 [ 항산균검사 ] 검체명 : Growth 된 AFB 상태 : 최종보고 접수일 :08/08/29 보고일 :08/09/09 NTM & MOTT 동정 Mycobacterium abscessus 최종 보고 08/07/07 일 검체 결과 입니다. 녹십자에서 시행한 검사입니다. TB 가 아니라는 것을 의미

22. AFB 배양 결과 및 균 동정 보고의 사례 (II)

23. Radiography of NTM lung disease Fibrocavitary formNodular/Bronchiectatic form Tranditional and most widely knownRecently recognized Middle-aged or eldely menMiddle-aged women Smoker, alcohol abuserNon-smoker Underlying disease COPD, previous TB, silicosis No underlying disease Similar to pulmonary TB, Upper lobeRML and Lingular segment of LUL Rapid progression (1 ~ 2 yrs) : lead to extensive lung destruction and death, if untreated Indolent and slow progression

24. Upper lobe cavitary form M/58, M. intracellulare

25. F/52, M. intracellulare

26. Radiography of NTM lung disease Fibrocavitary formNodular/Bronchiectatic form Tranditional and most widely knownRecently recognized Middle-aged or eldely menMiddle-aged women Smoker, alcohol abuserNon-smoker Underlying disease COPD, previous TB, silicosis No underlying disease Similar to pulmonary TB, Upper lobeRML and Lingular segment of LUL Relatively rapid progression (1 ~ 2 yrs) : lead to extensive lung destruction and death, if untreated Indolent and slow progression “Lady Windermere syndrome”

27. Nodular/bronchiectatic form Bronchiectasis/Bronchiolectasis Cellular bronchiolitis

28. Nodular/Bronchiectatic form F/52, M.abscessus

29. F/73, MAC Infection

30. F/79, MAC Infection

31. Cylindrical Bronchiectasis Saccular change (Honeycombing) Multiple small granulomas or abscess

32. Other forms of NTM - Pulmonary nodule(s) - 51 YO Female s/p breast ca. op PET-CT (SUV=11.5) Chronic granulomatous inflammation with caseation necrosis with no acid- fast bacilli. Tissue culture on Ogawa medium : M.abscessus Intern Med, 2006; 45; 169

33. Other forms of NTM - Pulmonary nodule(s) - Younsei Med J, 2007; 48; 127 45 YO femal, SPN in RUL PET-CT : SUV = 8.8 AFB 도말 (-), TB-PCR(-), cytology(-) in bronchial washing 5 wks later, AFB 배양 (3+), TB-PCR (-) on Ogawa medium PCR-RFLP method : M.intracelulare

34. 42 YO Female Multiple pulmonary nodules Cuture of tissue obtained by FNB : M.xenopi Other forms of NTM - Pulmonary nodule(s) -

35. Hot-tub Aerosolized droplets of NTM 르누아르의 목욕하는 여인들, 1918 ( 관절염 투병 중 ) 르누아르의 목욕하는 여인들, 1887

36. Other forms of NTM - Hypersensitivity pneumonitis - Am J Clin Pathol 2001; 115; 755

37. Other forms of NTM - Hypersensitivity pneumonitis - 54 YO female with cough, and dyspnea who recently purchased hot-tub Cultures of BAL fluid : M.intracellulare, TBLB : c/w HP Hot-tub lung

38. Radiologic findings of NTM lung disease according to NTM species SpeciesRadiologic findings M.avium complex (MAC) Upper lobe cavitary form (about 75%) thin-walled cavities in the upper lobes apical pleural thickening adenopathy, pleural effusion : uncommon Nodular bronchiectatic form bilateral nodular or reticulonodular infiltrates predominantly in the RML and Lingular segment multiple small nodules combined with BE at HRCT M.kansasii Thin-walled cavities in the upper lobes (95%) Pleural effusion, lower lobe involvement : uncommon RGM M. abscessus M. fortuitum M. chelonae Nodular bronchiectatic form Cavitation : uncommon

39. Bilateral BE and multiple nodules on CT Radiology, 2005, 235, 282

40. Diagnostic Limitations 45% of patients (14/31) : unable to produce sputum or negative sputum culture –Bronchoscopy with BAL/TBLB (n=13), Open lung Bx (n=1) Aggressive diagnostic approach, including bronchoscopy, should be considered if sputum cultures are negative Chest, 1999, 115, 1033 Culture for mycobacterial disease –Both solid and broth (liquid) media for detection and enhancement of growth National Committee for Clinical Laboratory Standards, 2003 –In most of Korean hospital including EWNMC, solid media has been only used for mycobacterial culture study

41. Recovery Rates for Mycobacteria 578 culture-positive specimens (Denver Health and Hospitals) % of mycobacteria recovered from: Liquid MediaSolid Meida BACTEC 12BMiddlebrook 7H11L-J media Positive culture 87%81%40% M. tuberculosis MAC M. kansasii 92% 86% 100% 86% 81% 93% 37% 44% 67% Negative culture 8%16%19% Contamination 5%3%41% J Clin Microbiol 1995;33:2516

42. Clinical (both required) 1. Pulmonary Sx Nodular or cavitary opacities on x-ray/CT that shows multifocal BE with multiple small nodules 2. Appropriate exclusion of other diagnoses Microbiologic 1. (+) culture from ≥ 2 separate expectorated sputum OR, 2. (+) culture from ≥ one bronchial washing or lavage OR, 3. Transbronchial or other lung Bx with mycobacterial histopathologic features + (+) culture for NTM or Bx showing mycobacterial histopathologic feature and one or more sputum or bronchial washing that are (+) culture for NTM 4. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination 5. Pts who are suspected of having NTM lung disease but do not meet diagnostic criteria should be followed until the diagnosis is firmly established or excluded 6. Dx of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy. 2007 ATS/IDSA Diagnostic Criteria These criteria have been best studied in infections d/t MAC, M.kansasii, and M.abscessus

43. NTM lung disease 진단되면 바로 치료를 시작해야 하나 ? Diagnosing pulmonary NTM infection/disease : Not equal to the need for immediate treatment

44. Natural History of MAC lung disease with nodular bronchiectasis 57 patients with MAC infection with nodular BE Observation duration : 28 ± 13 mo (12-42 mo) Deterioration (n=34, 60%) Not-deterioration (n=23, 40%) Spontaneous improvement (n=0) Lower BMI, older age, high neutrophil count, decreased CD4+lymphocyte in BALF, elevated CRP/ESR, CA19-9 in deterioration group Am J Respir Crit Care Med 1999;160:1851 Different natural history bwt fibrocavitaty form and N/BE form

45. 57 YO Woman: M. intracellulare Disease Apr. 1994Dec. 2001

46. Nov. 1998Sep. 2002 66 YO Woman: M. abscessus Lung Disease

47. Differences in Natural history of infection with different species/strains M.kansasii –More associated with a tuberculosis-like illness –Lower thresthold for treatment with antimicrobials M.szulgai –Rarely isolated from the environment –Single positive culture result is usually pathologically significant M.fortuitum –May not need to receive prolonged antibiotic therapy ? –No clinical aggravation during mean 12.5 mo F/U among 26 pts Respirology, 2009; 14; 12 Respir Med, 2008; 102; 437

48. Differences in Natural history of infection with different species/strains J Clin Microbiol, 2005; 43; 3150 Kaplan-Meier survival analysis of MAC patients with serovar 4 and those with other serovars. Log rank (Mantel-Cox) test, P < 0.05. Prognostic importance of serotyping MAC isolates

49. Medical Therapeutic Outcomes Treatment Outcomes of NTM lung disease –Pre-macrolide era Overall success rate (50-60%) with anti-TB agents Resectional surgery: essential to treat NTM lung disease Hattler BG et al, J Thorac Cardiovasc Surg 1970 Moran JF et al, Ann Thorac Surg 1983 –Introduction of newer macrolide (clarithromycin, azithromycin) Initial results of high success rate: 80-90% Overall success rate in the subsequent studies: 50-60% Wallace et al, AJRCCM 1994, Dauzenberg et al, Chest 1995 Griffith et al, Clin Infect Dis 2001, Huang et al, Chest 1999, Jeon K et al, 2006 ATS

50. Treatment Regimen for MAC (ATS) Initial Tx of nodular BE Initial Tx of cavitary disease Advanced or pretreated disease Macrolide Clarithromycin 1000mg, TIW500~1000mg/d Azithromycin 500~600mg, TIW250~300mg/d EMB 25mg/kg/d, TIW15mg/kg/d Rifamycin Rifampicin 600mg, TIW450-600mg/d Rifabutin 250-300mg/d Aminoglycoside (Sm or Am) None None or Am or Sm* Am or Sm Duration 12 mo culture negative * : Given intermittently for the first 2-3 months

51. Treatment Regimen for M.kansasii (ATS) Dosage EMB15 mg/kg/day RFP10 mg/kg/day (max: 600 mg/day) INH5 mg/kg/day (max: 300 mg/day) Duration12 months culture negative

52. Treatment for RGM lung disease Active drugsDurationSurgery M. abscessus clarithromycin amikacin, cefoxitin imipenem, linezolid, ciprofloxacin, doxycycline ? 12 mo++ M. chelonae tobramycin, clarithromycin linezolid, amikacin clofazimine, doxycyline ciprofloxacin ? 12 mo+ M. fortuitum amikacin, ofloxacin, ciprofloxacin, sulphonamide, clarithromycin, doxycyxline ? 12 mo+ Respirology, 2009; 14; 12

53. Surgery as adjuvant therapy Early pulmonary resection for localized MAC disease Conversion (31/33, 94%)Relapse rate (6%)1998 Surgery for MAC lung disease in the clarithromycin era Conversion (21/21, 100%)Relapse rate (9.5%)2001 Pneumonectomy for NTM infections Conversion (11/11, 100%)Relapse rate (9%)2004 Completion pneumonectomy for mycobacterial disease Conversion (14/17, 83%)NA2005 Surgical outcomes in KOREA Conversion (18/20, 90%)Relapse rate (0%) 2008

54. When to treat NTM lung disease 정말로 치료를 시작해야 할까 ? 기다려 볼까 ? 그 많은 약제를 잘 복용할 수 있을까 ? 뾰족한 약제 조합이 없고 … 근거도 부족하고 … 약값도 비싼데 … 부작용도 만만치 않고 … 치료 반응도 별로고 … 주사제를 사용해야 하나 ? 그렇다면 입원시켜야 하나 ? 언제까지 ? 수술은 해야하나 ?…

55. General Principles/Considerations Empiric therapy for suspected NTM lung disease is not recommended –Close F/U until Dx is firmly established or excluded Patient’s age and Potential for progressive parenchymal damage d/t NTM, leading to colonization /infection with other pathogens Presence of predisposing conditions –May affect the rate of progression of disease –Immunosuppressive medication, hereditary disorders of immune function very little pulmonary reserve (severe COPD, advanced BE) Toxic adverese effect ( versus benefit) from multi-drug regimen Drug-drug Interaction

56. General Principles/Considerations Need to establish realistic expectations regarding outcomes –In many patients, the aim should be CURE, and aggressive approach warranted. –In others, the aim should be SUPPRESSION OF DISEASE. M.abscessus : notoriously difficult to eradicate Cost, Age, Unclear impact of treatment on the QoL.

57. Thank you for your attention! Pulmonary and Critical Care Medicine Yee Hyung Kim M.D.