WHO DAT MOTT

2. WHO DAT MOTT Juzar Ali

3. Objectives and focus • NTM / MOTT Highlights • Some clinical examples • MAC in non-HIV population • Contemporary issues in management of MOTT / MAC -PD • References and supportive data available

4. Exposure Human to human transmission LTBI Latent disease Paucibacillary? Reactivation Incidence /Prevalence Relapse Environmental Ingestion No H-H transmission* * not even seen in CF * Paucibacillary Mixed infection Indolent New Infection Some basic differences TB /NTM

5. When the last ATS statement about NTM was prepared in 1997, there were approximately 50 NTM species that had been identified. Currently, more than 125 NTM species have been cataloged*** The increase relates to **improved microbiologic techniquesand identification New cases of NTM lung disease may significantly exceed case rates for TB in some communities and regions , **advances in molecular techniques with the development and acceptance of 16S rRNA gene sequencing as a standard for defining new species. ***Clinical significance??

6. Classification of mycobacterial species commonly causing human disease The “Staph” of mycobacteria

7. Pulmonary Disease M. abscessus : Worldwide; may be found concomitant with MAC M. asiaticum* Rarely isolated M. avium complex Worldwide; most common NTM pathogen in U.S. M. celatum* Cross-reactivity with TB-DNA probe M. kansasii : U.S., Europe, South Africa, coal-mining regions M. chelonae Pulm Disease ?? . M. fortuitum Associated with aspiration Contaminant M Szulgai and M Chelonae and Eye disease

8. Health Care– and Hygiene-associated Disease Prevention Prevention of health care–related NTM infections requires that surgical wounds, injection sites, and intravenous catheters not be exposed to tap water or tap water–derived fluids. Endoscopes cleaned in tap water and clinical specimens contaminated with tap water or ice are also not acceptable. MK / Tap Water MAC / Natural Water

9. **Lung disease due to NTM occurs commonly in structural lung disease, such as chronic obstructive pulmonary disease (COPD), bronchiectasis, CF, pneumoconiosis, prior TB, pulmonary alveolar proteinosis, and esophageal motility disorders **Abnormal CF genotypes, CFTR Gene mutation and _1-antitrypsin (AAT) phenotypes may predispose some patients to NTM infection **NTM lung disease also occurs in women without clearly recognized predisposing factors There is also an association between bronchiectasis, nodular pulmonary NTM infections and a particular body habitus, predominantly in postmenopausal women (e.g., pectus excavatum, scoliosis, mitral valve prolapse) “A mean MAC machine in the thin and lean” **Bronchiectasis and NTM infection, usually MAC, often coexist, making causality difficult to determine. These patients may carry multiple MAC strains over time, suggesting either polyclonal infection or recurrent infection with distinct strains). It is unclear whether this problem is due to local abnormalities (e.g., bronchiectasis) or to immune defects Am J Respir CC M 178; 1066-1074 , 2008 NHLBI

10. CRITERIA FOR DX

12. NTM - PD Profile Patient characteristics Microbiological Refractile Gram positive or Gram neutral rods AFB stains and growth on solid and liquid media (BACTEC or MGIT/ Mycobacteria growth indicator tube) Gene probes (HPLC) Lipid chromatography on smears and cultures within hours; some limitations In identification of MAb & MCh Imaging Others

13. Semi-quantitative analysis of smears can be useful for diagnostic and post Rx follow up purposes. The burden of organisms in clinical material is usually reflected by the number of organisms seen on microscopic examination of stained smears. Environmental contamination, which usually involves small numbers of organisms, rarely results in a positive smear examination. Previous studies have indicated that specimens with a high number of mycobacteria isolated by culture are associated with positive smears and, conversely, specimens with a low number of mycobacteria isolated by culture are less likely to have positive smears

14. Recommendation: ……. But the most important is Communication between the clinician and laboratories is essential for determining the importance and extent of the identification analysis for a clinical NTM isolate (C, III).

15. ATS Recommendations: 1. As much material as possible for NTM culture should be provided with clear instructions to the laboratory to culture for mycobacteria (C, III). 2. All cultures for NTM should include both a rapid detection broth (liquid) media technique and solid media cultures (C, III). 3. Quantification of the number of colonies on plated culture media should be performed to aid clinical diagnosis (C,III). 4. Supplemented culture media and special culture conditions (lower incubation temperatures) should be used for material cultured from skin lesions, joints, and bone (A,II 5. The time (in days) to detection of mycobacterial growth should be stated on the laboratory report (C, III).

17. MAC TB • Focus on HIV negative patients • MAC – PD • Environmental pathogen!!

18. The M. avium complex (MAC) includes M. avium, M. intracellulare, and a group of organisms referred to as the "X strains" which do not yet have a species designation. M. scrofulaceum was once grouped with these organisms as the "MAIS complex" (M. avium-intracellulare-scrofulaceum) While M. avium and M. intracellulare are also separate species, their separation has no clinical value for individual patients and is generally not performed. MAC typically produces small, flat, translucent, smooth colonies that occasionally exhibit a pale yellow color. These colony morphologies differ from M. tuberculosis, which typically shows cording in broth and appears as rough, buff colored colonies on agar.

19. MAC- PD classifications ? Radiographic: F/C or F/N bronchiectasis Immunological/structural /clinical: HIV Non- HIV ** immune , epithelial, mucociliary impairment or just an association • COPD: structural or airway clearance • LW Syndrome /Scoliosis/Pectus** • INF –G Il-12 mutation; CTFR

20. Pathophysiology of Bronchiectasis • The inflammation /infection cascade • Interleukin,8, neutrophils, unapposed elastase, and proteases • The effect of transmural inflammation, edema, crater formation, ulceration, and neovacularization leading to permaneent parenchymal damage • Different properties of sputum in dilated airways • Variance in mycobacterial genetic pool

21. Tumor Necrosis Factor Inhibition & NTM IFN-_ and IL-12 control mycobacteria in large part through the up-regulation of tumor necrosis factor (TNF)-_ made predominantly by monocytes/macrophages. The risk posed by TNF-_ blocking agents for predisposing to NTM infections or promoting progression of active NTM infection is unknown. Expert opinion is that patients with active NTM disease should receive TNF-_ blocking agents only if they are also receiving adequate therapy for the NTM disease.

22. A 52-year old Caucasian woman sought medical attention due to chronic cough. Physical exam was unremarkable. Sputum culture revealed light growth with few colonies of Mycobacterium avium complex (MAC). Repeat sputum cultures later again revealed a few colonies of MAC. The patient was treated symptomatically and followed clinically by serial sputum test (s) and radiographic evaluation. No specific therapy for MAC was initiated and the patient did well, remaining asymptomatic.

23. : Wheezing; Dx Asthma CXR Nodular opacities ? TB Started RIPE Tr Bx Bx: Granulamatous Inflammation Br Wash: MAC MAC “Hot tub Lung” ; or Sarcoidosis with MAC?

24. Epidemiology. MAC exposure associated with hot-tub lung represents a commonly recognized form of hypersensitivity-like NTM pulmonary disease. NTM other than MAC also have the potential to result in hypersensitivity-like lung disease associated with hot tubs. Role of indoor showerheads???

25. Microbiologic data are critical for the diagnosis of MAC hypersensitivity-like lung disease, but not in isolation nor without clinical, radiographic, or pathologic findings consistent with MAC hypersensitivity-like disease. The histopathology is that ofnon necrotizing granulomas although necrotizing granulomas, organizing pneumonia, or interstitial pneumonia may also be described in some patients The distribution of these discrete granulomas is generally centrilobular and bronchiocentric, differentiating MAC hypersensitivity like lung from sarcoidosis or other hypersensitivity pneumonitis.

26. TB? RIPE MK MAC MAN!! The Mycobacterial Highway/ Route A

27. MOTT “Migration dilemma” • Fibrocavitary disease • PPD positive • MAC by culture • Repeat Sputum: M.Chelonei • Rx or not?]\ • What to Rx? • Rx LTBI??

28. The significance of two NTM species isolated simultaneously from a patient is also unknown. The combination of MAC and M. abscessus is especially well recognized. on an individual basis. Both these events are likely to occur with increased frequency because of improved recovery of NTM by mycobacteriology laboratories.

29. A 76- year old Caucasian woman, smoker, with past history of TB, treated completely in the 1960’s, was seen with cough and minimal shortness of breath. Pulmonary function tests revealed moderate obstructive airways dysfunction. Sputum tests revealed moderate growth of Mycobacterium avium complex on repeated examinations. The patient was placed on daily treatment with clarithromycin and ethambutol with bronchodilators. She remained stable on this regimen without any acute exacerbations. Serial sputum cultures intermittently revealed light growth of Mycobacterium avium complex.

30. A 65-year old woman with a history of nonspecific interstitial pneumonitis (NSIP) and pulmonary fibrosis and with documented Mycobacterium avium complex (MAC) on repeated sputum cultures since 2003 was admitted in March 2006 with increasing dyspnea and respiratory failure. Prior to admission she had had multiple sputum cultures which were positive forMAC and sensitive only to high dose clarithromycin, ethambutol and rifabutin with which she was treated for 18 months. Due to concomitant and repeated growth of methicillin-resistant Staphylococcus aureus (MRSA), she was also given linezolid intermittently. She was admitted to the hospital and treated empirically with broad-spectrum antibiotics while her MAC treatment was continued due to persistently positive sputum cultures. She failed to respond to therapy and died after a month of hospitalization due to progressive respiratory failure.

31. A 42-year old man with history of treated TB in 1980 developed fibrocavitary MAC infection in 1993. His treatment with ethambutol, rifabutin and clarithromycin was erratic due to non-adherence. He was admitted to the hospital in March 2004 with increasing cough, night sweats and a ten pound weight loss. No culture and sensitivity data were available. With the history of erratic treatment, presumed macrolide resistance and unilateral fibrocavitary right sided disease, he was evaluated for surgical excision and pneumonectomy. His pulmonary function tests revealed a FEV1 of 1.4 L and a split perfusion pulmonary scan showed one percent perfusion of the right lung and 99% of blood flow to the left lung. The patient had a complicated operative and perioperative course and died of respiratory failure after a month long stay in the ICU.

32. : Culture positive TB on Rx; Subsequent 7 sputa all culture negative for TB , positive for MAC Figure 6

33. A 50-year old man with severe COPD and bronchiectasis was on long term treatment for Mycobacterium avium complex pulmonary disease (MAC-PD) initially and later for macrolide-resistant MAC (MRMAC). He was admitted in moderately severe respiratory distress with fever and increasing cough. In addition to the multiple drugs used for the treatment of this patient though the course of his illness, therapeutic trials of thalidomide, interferon gamma and high dose mefloquine were given. Due to progressive bilateral disease and poor pulmonary function, surgery was not considered. (The patient later died of respiratory failure and overwhelming infection.

34. Because no correlation between in vitro susceptibility results for MAC and clinical response for agents other than macrolides has been established, the 2003 CLSI document states that clarithromycin is the only drug for which susceptibility testing for MAC isolates is recommended

35. Suggested algorithm for Culture & Sensitivity Macrolide/Azalide Sensitive No Do Expanded Sensitivity Consider combination Rx sensitivity Such as Rif /Rb with Eth Yes Rx with macrolide/Azalide Combination double or triple Drug Rx

36. Untreated MAC isolates usually have minimum inhibitory concentrations (MICs) of 4 _g/ml or less to clarithromycin and are considered susceptible. In contrast, relapse strains after treatment inevitably have a clarithromycin MIC of 32 _g/ml or greater and no longer respond to treatment with macrolides

37. Isolates of MAC have only a single copy of the ribosome, and hence, macrolide monotherapy carries a significant risk of the development of mutational resistance. All high-level clarithromycin-resistant isolates have mutations in the adenine at position 2058 or 2059 of the 23S rRNA gene, which is the presumed macrolide binding site on the ribosomal unit

38. MANAGEMENT OPTIONS Step 1: Diagnosis & Clinical Classification** ** Ref: 5. American Thoracic Society Documents: Mycobacterial Diseases Subcommittee. The Official Statement of the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) Am J Respir Crit Care Med Vol 175. pp 367–416, 2007 ** Ref 9 Chitty S, Ali J. Mycobacterium Avium Complex Pulmonary Disease in immune competent patients. Southern Medical Journal June 2005, 98 (6) pp 646-652 Surveillance Group Treatment Group Suppressive treatment Group Clinical and chest-imaging follow-up with serial sputum cultures and colony counts; ?also applicable in the “Hot Tub Lung Group” Based on risk-benefit analysis: Suppressive treatment with two drugs: ETHAMBUTOL & MACROLODE Step 2: CATEGORIZE GROUP Aggressive treatment group FOCAL DISEASE DIFFUSE NODULAR FIBROCAVITARY COMPLEX BRONCHIECTASIS DISEASE MACROLIDE RESISTANT 3 drugs +- SURGERY 3 DRUGS THRICE 3 DRUGS DAILY plus IV CUSTOMIZED WEEKLY AMINOGLYCOSIDE PROTOCOL

39. A potential consequence of the broad adoption of the low-dose and long-term azithromycin therapy in patients with CF is the evolution of macrolide-resistant NTM. A careful evaluation for possible pulmonary NTM infection, including multiple sputum cultures for NTM, should precede any initiation of macrolide monotherapy, and cultures for NTM should be obtained periodically thereafter.

40. Factors contributing to the poor response to therapy included cavitary disease, previous treatment for MAC lung disease, and a history of chronic obstructive lung disease or bronchiectasis and macrolide resistance,

41. Recommendations: 1. Surgical resection of limited (focal) disease in a patient with adequate cardiopulmonary reserve to withstand partial or complete lung resection can be successful in combination with multidrug treatment regimens for treating MAC lung disease (B, II). 2. Surgical resection of a solitary pulmonary nodule due to MAC is considered curative (C, III). 3. Mycobacterial lung disease surgery should be performed in centers with expertise in both medical and surgical management of mycobacterial diseases (C, III).

42. MAC success story At least one !!!! At start of Rx

43. After 18 months of Rx and culture negativity Follow up?? Imaging, cultures, Gallium scan, Serology?

46. M. Chelonei • 83 year old man, pre op CXR LUL nodular and cavitary disease; AFB positive, TBS test positive , started on RIPE , referred from our Baptist Campus ; later all cultures grew M Chelonei • Issues and options?? Discussion ; do ATS criteria apply ?? ; special considerations?..look out for ???

47. Other MOTT • 60 year old , PPD 22 mm, TBS borderline x 3 ; sputum AFB positive • Cultures MK* and or M szulgai • CT next • Rx? • What and how • Lab confusion • * key determinant in Rx plan…

48. Eye on MOTT continued:MOTT in EYE • 27 year old, PPD positive 12 mm ; TB spot negative , uveitis , granuloma , decreased visual acuity • Past history of lasik surgery • 80 year old , history of cataracts PPD positive , TB spot positive , granulomatous iritis and uveitis • Culture data usually NA; Stress on PCR • Consider MOTT as cause

49. A “red herring” / a source search • The MOTT/ FAC bugs………….. • M. Szulgai ………………. • M. Gordonae…………….

50. Points to remember • Pulmonary disease due to RGM is predominantly due to M. abscessus (80 percent of cases) and M. fortuitum (15 percent of cases)]. Various series have emphasized associations of RGM pulmonary infection with esophageal disease malignancy], underlying lung disease [], and rheumatologic conditions [