1. Ira Finegold, MD Chief of Allergy, St Luke’s-Roosevelt Hospital Center, NYC Clinical Professor Medicine, College of Physicians and Surgeons, Columbia University, New York Past President ACAAI

2. Ira Finegold,MD

3. Learning Objectives: 1.To review the many causes of persistent cough. 2.To Become aware of the role non tuberculous mycobacteria may play in patients with prolonged coughs

4. Cough : Common Causes  Smoking and other environmental irritants  Postnasal drip  Asthma  Gastroesophageal reflux  Chronic bronchitis  Transient airway hyperresponsiveness (e.g., after viral upper respiratory infection)  Medication-related (ACE inhibitors, beta blockers

5. Cough: Uncommon causes  Congestive Heart Failure  Cancer (bronchogenic or esophageal)  Interstitial lung disease (emphysema or sarcoidosis)  Bronchiectasis  Tuberculosis and other chronic lung infections (e.g., fungal) Cystic fibrosis  Recurrent aspiration (e.g., post-stroke, frequent vomiting [bulimia], alcoholism)

6. Cough: Uncommon causes  Pressure from an intrathoracic mass (e.g., thoracic aneurysm, thyromegaly, mediastinal lymphadenopathy)  Irritation of cough receptors in ear (e.g., impacted cerumen, hair, foreign body)  Opportunistic infections in immunosuppressed patients  Lymphangitis carciomatosis  Foreign body  Chronic inhalation of bronchial irritants (occupational)  Psychogenic

7. EG  DOB: 1939  WF Executive  History of pollen allergy and frequent infections in childhood  Bronchiectasis, and positive NTM 1999.

8. EG  Symptoms: Cough, Dyspnea, Night sweats, weight loss and fatigue. No fever  PE: Unremarkable –thin WF

9. EG LAB  1999: IgG said to be normal  2/14/05 IgG 686  8/11/06 IgG 765  7/10/2007 IgG 820 IgG2 decr.  Sputum cultures:  Many positive for m.avium, m. abcessus

10. EG LAB  CT SCAN 5/07 Abnormal, recently improving, brochiectasis  5/21/07 WBC : 3,770 Monocytes 12.7%  IgE : 269  multiple drug allergies

11. EG Meds  Tigecycline IV  Clarithromycin  Ethambutol  Rifampin  Moxifloxacin  Sulfamethoxazole/trimethoprim  Fluconazole, Tiotropium

12. NTM Morphotype  Middle aged white females  Slender, tall,  Scoliosis, Pectus excavatum  Mitral Valve prolapse  Higher percentage of CFTR genes  No cellular immune defects Iseman & Marras AJRCCM 178:999, 2008, Kim et al. 1066-1074.

13. Kim, et al. Pulmonary Nontuberculous Mycobacterial Disease Am J Resp Crit Care Med 178:1066, 2008

16.  Mycobacteria are a family of small, rod-shaped bacilli.  The most recognized of the family are M. tuberculosis (TB) and M. leprae ( Hansen’s Disease or leprosy).  Unlike TB and leprosy, which are primarily spread human-to-human, the NTM are believed to be acquired from the environment - hence the alternative label, “environmental mycobacteria.” 4/21/2015 What are the NTMs? Nontuberculous Mycobacterial Lung Disease

17. NTM Pulmonary* Pathogens Nontuberculous Mycobacterial Lung Disease Common M. avium M. intracellulare M. kansasii M. abscessus M. chelonae (kell oh’ nye) Infrequent M. xenopi (zin oh’ pee) M. szulgai (sull’ guy) M. malmoense (mal’ moh en suh) M. fortuitum *Other NTMs are very rare pulmonary pathogens but may present as extrapulmonary pathogens; see ATS guidelines } MAC

18. NTM Pulmonary* Pathogens Nontuberculous Mycobacterial Lung Disease Rare M. celatum (sell ah’ tum) M. scrofulaceum M. simiae M. terrae M. immunogenum Never (almost) M. gordonae *Other NTMs are very rare pulmonary pathogens but may present as extrapulmonary pathogens; see ATS guidelines

19. Mycobacterium avium complex lung disease Background  Not reportable disease - historically  1979-80 : NTM 1/3 of all mycobact isolates  1990-91 : NTM 3/4 of all mycobact isolates  Increased prevalence not well characterized  Historically, case rate (MAC) estimated between 0.9 and 4.6 per 100,000  Ontario: ’97-’99 - 6.3/100k to ’01-’03 9.3/100k ( U.S. TB case rate 2004 4.9 / 100,000) NNNNot reportable disease - historically 1111979-80 : NTM 1/3 of all mycobact isolates 1111990-91 : NTM 3/4 of all mycobact isolates IIIIncreased prevalence not well characterized HHHHistorically, case rate (MAC) estimated between 0.9 and 4.6 per 100,000 OOOOntario: ’97-’99 - 6.3/100k to ’01-’03 9.3/100k ( U.S. TB case rate 2004 4.9 / 100,000)

20. Mycobacterium avium complex lung disease Background  Now more than 125 identified NTM species  MAC (Mycobacterium avium complex) most common  Ubiquitous: soil and water  Animal to human and human to human transmission not documented  Asymptomatic infections and symptomatic disease in humans possible  Now more than 125 identified NTM species  MAC (Mycobacterium avium complex) most common  Ubiquitous: soil and water  Animal to human and human to human transmission not documented  Asymptomatic infections and symptomatic disease in humans possible

21. Diagnosis and treatment of lung infection with nontuberculous mycobacteria Arend et al. Current Opinion in Pulmonary Medicine 2009,

22. NTM Infections in New Hosts  Over the past 25 years, there has been a dramatic increase in the number of NTM cases seen by pulmonary and ID clinicians across the U.S.  The epidemiology has changed - now predominantly seen in Caucasian women of middle age and older  Usually with a negative or negligible smoking history  Commonly with a slender body habitus Nontuberculous Mycobacterial Lung Disease

23. The New NTM ATS Guidelines AJRCCM 175: 367-416, 2007 Similar diagnostic criteria for MAC and NTM lung diseaseSimilar diagnostic criteria for MAC and NTM lung disease 3 of 3 criteria required:3 of 3 criteria required: History and physical exam - clinical presentationHistory and physical exam - clinical presentation Chest radiography / Chest CTChest radiography / Chest CT Microbiology / histopathologyMicrobiology / histopathology Similar diagnostic criteria for MAC and NTM lung diseaseSimilar diagnostic criteria for MAC and NTM lung disease 3 of 3 criteria required:3 of 3 criteria required: History and physical exam - clinical presentationHistory and physical exam - clinical presentation Chest radiography / Chest CTChest radiography / Chest CT Microbiology / histopathologyMicrobiology / histopathology

24. Mycobacterium avium complex lung disease Clinical Presentation Variable presentation: Group 1 : Preexisting lung disease Group 2 : No previous lung disease Group 3 : Hot tub lung (HTL) Group 4 : HIV Group 5 : Interleukin-12 /  -IFN defects Variable presentation: Group 1 : Preexisting lung disease Group 2 : No previous lung disease Group 3 : Hot tub lung (HTL) Group 4 : HIV Group 5 : Interleukin-12 /  -IFN defects

25. Mycobacterium avium complex lung disease Clinical Presentation  Markedly abnormal pulmonary function tests  Associated diseases: COPD, past granulomatous lung disease (TB, fungal), radiation fibrosis, bronchiectasis, silicosis  CF: increased recognition of MAC as well as other NTM  Markedly abnormal pulmonary function tests  Associated diseases: COPD, past granulomatous lung disease (TB, fungal), radiation fibrosis, bronchiectasis, silicosis  CF: increased recognition of MAC as well as other NTM Group 1 : Preexisting lung disease Group 1 : Preexisting lung disease

26. Mycobacterium avium complex lung disease Clinical Presentation Group 1 : Preexisting lung disease  Localized or diffuse fibrocavitary disease  Male predominance: smokers  Age: 6th to 8th decade Group 1 : Preexisting lung disease  Localized or diffuse fibrocavitary disease  Male predominance: smokers  Age: 6th to 8th decade

27. Mycobacterium avium complex lung disease Clinical Presentation Group 2 : No previous lung disease (Most common) Mild abnormal pulmonary function tests: obst, restrictive, mixed Associated findings: mitral valve prolapse, pectus excavatumAssociated findings: mitral valve prolapse, pectus excavatum Functional IFN-  defects not detected; increased CFTR mutations notedFunctional IFN-  defects not detected; increased CFTR mutations noted Mild abnormal pulmonary function tests: obst, restrictive, mixed Associated findings: mitral valve prolapse, pectus excavatumAssociated findings: mitral valve prolapse, pectus excavatum Functional IFN-  defects not detected; increased CFTR mutations notedFunctional IFN-  defects not detected; increased CFTR mutations noted

28. Common Features of NTM Lung Disease  Clinical :  Insidious onset of cough; initially dry, then variably productive of mucopurulent secretions; occasionally bloody. Cough may be precipitated by lying down.  Dyspnea  Fever, chills, night sweats are not uncommon  Recurrent “bronchitis,” or “walking pneumonia”  Vague malaise and diminished energy  Occasionally, focal chest discomfort Nontuberculous Mycobacterial Lung Disease

29. Mycobacterium avium complex lung disease Radiographic Findings  Nodular infiltrates  Cavity and fibrocavitary disease with or without thickened walls  Consolidation  Solitary or multiple pulmonary nodules  Cylindrical, cystic, or saccular bronchiectasis ___________________________________________  *Pleural disease, prominent mediastinal/hilar adenopathy, air-fluid levels, and on high resolution chest computed tomography are not commonly associated with MAC in patients with MAC-PD associated with preexisting disease. Ground glass opacities common (HTL) may be present.  Nodular infiltrates  Cavity and fibrocavitary disease with or without thickened walls  Consolidation  Solitary or multiple pulmonary nodules  Cylindrical, cystic, or saccular bronchiectasis ___________________________________________  *Pleural disease, prominent mediastinal/hilar adenopathy, air-fluid levels, and on high resolution chest computed tomography are not commonly associated with MAC in patients with MAC-PD associated with preexisting disease. Ground glass opacities common (HTL) may be present.

30. Common Features of NTM Lung Disease  Chest Radiography:  Chest X-rays typically reveal amorphous, lower zone shadowing  Upper lobe cavitary disease (like TB) is uncommon; however, cavities may be present in other zones  High Resolution Computed Tomography (HRCT) lung scans are the primary diagnostic aid in recognizing NTM disease  HRCT scans often reveal predominantly right middle lobe and/or lingular disease Nontuberculous Mycobacterial Lung Disease

31. NTM Infection Presentation Nontuberculous Mycobacterial Lung Disease Common CXR findings: A.Hazy opacity abutting the heart border [#1] 1

32. Common CXR findings: B.Retrosternal shadowing overlying the cardiac silhouette [#2] Nontuberculous Mycobacterial Lung Disease NTM Infection Presentation 2

33. Nontuberculous Mycobacterial Lung Disease Common HRCT scan findings: A.Volume loss and variable opacities of the right-middle lobe (RML) and lingular segment of the left-upper lobe (LING) B. Saccular or “honeycomb” bronchiectasis in both the RML & LING C. Diffuse cylindrical and varicoid bronchiectasis with scattered nodular opacities [RML] [LING]

34. Mycobacterium avium complex lung disease: Microbiology / histopathology  Sputum/wash: multiple positive cultures, smears; > 2  Single wash available w/o sputum: positive culture, independent of smear  Tissue: culture positive, granulomas w/ positive sputum/wash  Sputum/wash: multiple positive cultures, smears; > 2  Single wash available w/o sputum: positive culture, independent of smear  Tissue: culture positive, granulomas w/ positive sputum/wash ATS: AJRCCM 175: 367, 2007

35. Mycobacterium avium complex lung disease Natural History Colonization?Colonization? InfectionInfection Disease (treatment) Diagnosis = Treatment ??? Diagnosis = Treatment ???

36. Mycobacterium avium complex lung disease Natural History Limited data, esp. those w/o pre-existing lung disease and immunocompetent Slow progression (years), non-cavitary nodular with cylindrical bronchiectasis Culture conversion not likely to occur with bronchial hygiene alone when ‘infection’ present Limited data, esp. those w/o pre-existing lung disease and immunocompetent Slow progression (years), non-cavitary nodular with cylindrical bronchiectasis Culture conversion not likely to occur with bronchial hygiene alone when ‘infection’ present

37. Mycobacterium avium complex lung disease Natural History Spectrum of disease: mild symptoms to respiratory failure/death-advanced lung disease Clinical and microbiologic status parallel Relapse possible post-treatment Spectrum of disease: mild symptoms to respiratory failure/death-advanced lung disease Clinical and microbiologic status parallel Relapse possible post-treatment

38. Mycobacterium avium complex lung disease Treatment Overall sputum conversion rates 78% Overall sputum conversion rates 78% Previously treated conversion rates 55-64% Previously treated conversion rates 55-64% Naïve treatment patient conversion 74-92% Naïve treatment patient conversion 74-92% Non-cavitary disease 82-92% Non-cavitary disease 82-92% Fibrocavitary disease 74% Fibrocavitary disease 74% Overall sputum conversion rates 78% Overall sputum conversion rates 78% Previously treated conversion rates 55-64% Previously treated conversion rates 55-64% Naïve treatment patient conversion 74-92% Naïve treatment patient conversion 74-92% Non-cavitary disease 82-92% Non-cavitary disease 82-92% Fibrocavitary disease 74% Fibrocavitary disease 74% Aksamit,T.R. et al. AJRCCM 161:A725,2000 Griffith, D.E. et al. Clin Infect Dis 30:288,2000 Tanaka, E. et al. AJRCCM 160: 866, 1999 Dautzenberg, B. et al. Chest 107: 1035,1995 Aksamit,T.R. et al. AJRCCM 161:A725,2000 Griffith, D.E. et al. Clin Infect Dis 30:288,2000 Tanaka, E. et al. AJRCCM 160: 866, 1999 Dautzenberg, B. et al. Chest 107: 1035,1995

39. Elements of NTM Disease Diagnosis  Clinical History (Demographics)  Radiography  Microbiology  A. Spontaneous sputum sample  B. Induced sample (hypertonic saline nebs)  C. Bronchoscopy, if A and B fail to yield results  D. Be sure to culture for other potential bacterial and fungal pathogens Nontuberculous Mycobacterial Lung Disease

40. Clinical Presentations Recap:  Chronic cough - variably productive for years  Fatigue, often severe  Malaise  Weight loss  Night sweats  Feverishness *Some of these symptoms can also be attributed to menopause, possibly leading to a delay in diagnosis 4/21/2015 Symptoms Nontuberculous Mycobacterial Lung Disease

41. Possible predisposing or co-existing conditions:  Cystic Fibrosis, including adult-onset variants  Primary ciliary dyskinesia (immotile cilia or Kartagener’s Syndrome)  Alpha-1 antitrypsin anomalies  GERD with aspiration  Prior histoplasmosis or TB  HIV, Immunosuppresive drugs, Anti TNF-α Nontuberculous Mycobacterial Lung Disease

42. American Thoracic Society (ATS) Diagnostic Criteria  Originally published in 1997; revised 2007  Critical issue: since the NTM are widespread in the environment, a single isolation is usually NOT sufficient for diagnosis/initiation of therapy  General guidelines for the typical NTMs (MAC., M. abscessus)  A) 2 or more (+) cultures  B) or a (+) smear and (+) culture  C) or (+) bronch wash culture Am. J. Respir. Crit. Care Med. 175:367-416, 2007 Nontuberculous Mycobacterial Lung Disease

43. Treating Pulmonary NTM Infection  ATS guidelines describe chemotherapy options; basic principle - analogous to TB- use multiple drugs to increase efficacy and to prevent acquired resistance.  ATS guidelines usually suggest standard regimens based on accurate identification of species, e.g. regimen “X” for M. kansasii.  Role of in vitro susceptibility (s) testing is debated  consistent agreement for in vitro (s) testing for macrolides in MAC;  standard panel for rapidly-growing NTMs, such as M. abscessus or M. chelonae; Nontuberculous Mycobacterial Lung Disease

44. 2007 ATS Guidelines for Treatment of MAC: 1.Initial Rx for nodular-bronchiectatic disease is TIW a. Clarithromycin 1000 or azithromycin 500 mg b. Ethambutol 25 mg/kg c. Rifampin 600 mg 2. Initial RX for fibrocavitary or severe nodular- bronchiectatic disease is DAILY a. Clarithromycin 500-1000 or azithromycin 250 mg b. Ethambutol 15 mg/kg c. Rifampin 10 mg/kg to maximum 600 3. Goal: 12 months of negative cultures while on therapy 4. Surgery may be useful in localized disease Am J Respir Crit Care Med 175:367-416, 2007

45. Mycobacterium avium complex lung disease Treatment Observation Observation Medical therapy : Triple drug therapy Medical therapy : Triple drug therapy Clarithromycin /azithromycin, rifampin/rifabutin, ethambutol +/- streptomycin/amikacin first 2-3months 12 month culture negativity Role of quinolones, clofazimine, others ? Adjunctive therapy: Adjunctive therapy: Recent negative inhaled IFN-  trial Observation Observation Medical therapy : Triple drug therapy Medical therapy : Triple drug therapy Clarithromycin /azithromycin, rifampin/rifabutin, ethambutol +/- streptomycin/amikacin first 2-3months 12 month culture negativity Role of quinolones, clofazimine, others ? Adjunctive therapy: Adjunctive therapy: Recent negative inhaled IFN-  trial ATS: AJRCCM 175: 367, 2007

46. Mycobacterium avium complex lung disease Treatment Surgery Surgery Other contributing factors: Other contributing factors: Bronchiectasis, GERD, sinus disease Hot Tub Lung : Ag removal +/- steroids, antimycobacterial Rx Hot Tub Lung : Ag removal +/- steroids, antimycobacterial Rx Surgery Surgery Other contributing factors: Other contributing factors: Bronchiectasis, GERD, sinus disease Hot Tub Lung : Ag removal +/- steroids, antimycobacterial Rx Hot Tub Lung : Ag removal +/- steroids, antimycobacterial Rx ATS: AJRCCM 175: 367, 2007

47. Mycobacterium avium complex lung disease AJRCCM 175: 367-416, 2007 CONTROVERSIES:  Is one macrolide, clarithromycin or azithromycin, superior to another in the treatment of MAC lung disease?  Does the inclusion of an injectable agent early in the treatment of MAC lung disease improve long-term outcome?  Is one rifamycin, rifabutin or rifampin, superior to another in the treatment of MAC lung disease? CONTROVERSIES:  Is one macrolide, clarithromycin or azithromycin, superior to another in the treatment of MAC lung disease?  Does the inclusion of an injectable agent early in the treatment of MAC lung disease improve long-term outcome?  Is one rifamycin, rifabutin or rifampin, superior to another in the treatment of MAC lung disease?

48. 2007 ATS Guidelines for Treatment of M. kansasii Summary of ATS Recommendations for M. kansasii therapy 1.Daily regimen might include: a. Rifampin 10 mg/kg/day to maximum 600 mg b. Ethambutol 15 mg/kg/day c. Isoniazid 5 mg/kg/day to maximum 300 mg* 2.Goal: 12 months of negative cultures while on therapy * Recent data suggest that macrolides (clarithromycin or azithromycin) may be substituted for INH; not part of ATS Recommendations. Am J Respir Crit Care Med 175:367-416, 2007

49. 2007 ATS Guidelines for Treatment of M. chelonae- abscessus Summary of ATS Recommendations for M. abscessus* Therapy 1.The only predictably curative therapy of limited (focal) M. abscessus lung disease is surgical resection combined with multidrug chemotherapy. 2.Periodic multidrug therapy (a macrolide and 1 or more parenteral agents including amikacin, cefoxitin or imipenem or a combination of the parenteral agents) may help control symptoms and/or progression of disease. * Management of M. chelonae disease is analogous. Am J Respir Crit Care Med 175:367-416, 2007

50. Complementary Elements of Therapy  Patients with bronchiectasis often benefit from bronchial hygiene:  Airway agitating devices (Acapella ®, Flutter ® or Pep valves)  Inhaled bronchodilating/anti-inflammatory agents, including  -agonists, anti-cholinergics and/or steroids  If patient has co-existing sinusitis (a common finding), management may improve cough  GERD, if present (also a common finding), may provoke cough and periodically soil the lungs. Acid-inhibition may not be sufficient; may need measures to prevent reflux (posture in bed, meal patterns or, rarely, surgical repair). Nontuberculous Mycobacterial Lung Disease

51. Management Strategies:  Duration:  Varies widely by patient, disease severity and tolerance to medications  Average duration is 12-24 months  Rapidly growing NTM infections may require intermittent treatment across lifetime 4/21/2015 Nontuberculous Mycobacterial Lung Disease

52. Management Strategies:  Objectives:  Improved quality of life and overall strength  Significant reduction in constitutional and radiographic symptoms  Traditionally, sputum sterilization was the goal; still important, but not sufficient 4/21/2015 Nontuberculous Mycobacterial Lung Disease

53. Management Strategies:  Surgery:  Surgical resection may be an option for localized disease.  Debulking of diseased tissue may significantly reduce symptoms and the spread of disease in some patients.  Strongly consider referral to a specialty center when considering surgery. 4/21/2015 Nontuberculous Mycobacterial Lung Disease

54. Respondent Characteristics  Gender  38 (83%) women  8 (17%) men  Race  45 (98%) White  1 Native American  Employment  20 (43%) employed  26 (57%) not employed  Age  Range: 15-80  Median: 60 years  Mean (SD): 59 (11)

55. Onset and Diagnosis  Age at onset of symptoms  Range: 3-78 years old  Median: 55  Mean (SD): 52 (16)  Years from symptoms to diagnosis  Range: 0-30 years  Median: 1  Mean (SD): 4 (6)

56. NTM Medication Use  Took meds for NTM  34 (74%) yes  12 (26%) no  Cycles of therapy  Range: 0-20 cycles  Median: 1  Mean (SD): 1 (3)

57. Condition in Last 12 Months  Culture (22 responses)  13 (59%) Still positive  9 (41%) Converted to negative  X-ray (33 responses)  8 (24%) worsened  25 (76%) not worsened  Symptoms— cough, hemoptysis, weight loss, loss of appetite, fatigue, shortness of breath, fever, depression (41 responses)  21 (51%) at least one symptom worsened  20 (49%) not worsened

58. Consultation  Many cases of NTM Lung Disease are difficult to manage  Early consultation may be helpful:  Referrals -  Informational - this site provides free informational sources:  www.NTMinfo.org  Referrals -  Regional specialists  National referral programs:  Mayo Clinic  National Jewish Medical and Research Center  Stanford University  University of Texas, Tyler Nontuberculous Mycobacterial Lung Disease

59. Who doesn’t ‘have’ NTM?  Findings may represent colonization of the lower respiratory tract  CF patients 13% positive culture  Some organisms are unlikely pathogens  Eg M. gordonae

60. Other patients seen in one year  PF 70 yo wf history of AR Chest x-ray bronchiectasis, m.abcesses  EG 67 wf Sickly child, brochiectasis m. abcessus, m. avium, multiple drug allergies, IgE 269, IgG 686  EK 73 yo WF Rx’d for TB age 8, 18,26, Bronchiectasis, Nl IgG  MR 61 yo WF coughing for 5 years, M. avium complex  TH 46 yo WF coughing 6 years, Thyroid surgery, Calcium 7.8, IgG 660 IgG1 and 4, IgE 14 MAC  AJ: 51 HF Health aid m. avium  RM 63 yo WM α1 antitrypsin, 2 yrs previously MAC IgE:12  RY 62 yo wm smoker COPD IgE 122, IgG 859 MAC  KK 46 yo wf. Nl IgG Biopsy NTM Granulomas

61. Serum IgG Levels in NTM Patients

62. Immunopathology  Central to pathogenisis of MTB- Failure to contain organism  Defects in IL-12, IFN-γ  Expression of IL-8, FOXP3, IL-12β can distinguish between latent and active TB * *Wu, Huang et al. J Immunol 178:3688, 2007

63. Immunopathology NTM KIM AJRCCM:2008  Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-γ/IL-12 pathway. CD41, CD81, B, and natural killer cell numbers were normal.  A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene

64. Take Home Lesson  For patients with chronic productive coughs defying diagnostic maneuvers and not responding to conventional therapy,  Consider the possibility of NTM and order sputums for AFB stain and Culture and sensitivity

66. Questions and Thank you!