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 COUGHING UP ATYPICAL MYCOBACTERIA: A NEW EPIDEMIC Ira Finegold,MD I HAVE NO ACTUAL OR POTENTIAL CONFLICTS OF INTEREST TO DECLARE. Learning Objectives: 1. To review the many causes of persistent cough. 2. To Become aware of the role non I tuberculous mycobacteria may play in patients with prolonged coughs 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 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) 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 EG DOB: 1939 WF Executive History of pollen allergy and frequent infections in childhood Bronchiectasis, and positive NTM 1999. EG Symptoms: Cough, Dyspnea, Night sweats, weight loss and fatigue. No fever PE: Unremarkable –thin WF 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 EG LAB CT SCAN 5/07 Abnormal, recently improving, brochiectasis 5/21/07 WBC : 3,770 Monocytes 12.7% IgE : 269 multiple drug allergies EG Meds Tigecycline IV Clarithromycin Ethambutol Rifampin Moxifloxacin Sulfamethoxazole/trimethoprim Fluconazole, Tiotropium 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. Kim, et al. Pulmonary Nontuberculous Mycobacterial Disease Am J Resp Crit Care Med 178:1066, 2008 Kim, et al. Pulmonary Nontuberculous Mycobacterial Disease Am J Resp Crit Care Med 178:1066, 2008 Kim, et al. Pulmonary Nontuberculous Mycobacterial Disease Am J Resp Crit Care Med 178:1066, 2008 Nontuberculous Mycobacterial Lung Disease What are the NTMs? 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.” 4/13/2011 Nontuberculous Mycobacterial Lung Disease NTM Pulmonary* Pathogens Common Infrequent M. avium M. xenopi (zin oh’ pee) M. intracellulare } MAC M. szulgai (sull’ guy) M. kansasii M. malmoense M. abscessus (mal’ moh en suh) M. chelonae (kell oh’ nye) M. fortuitum *Other NTMs are very rare pulmonary pathogens but may present as extrapulmonary pathogens; see ATS guidelines Nontuberculous Mycobacterial Lung Disease NTM Pulmonary* Pathogens Rare Never (almost) M. celatum (sell ah’ tum) M. gordonae M. scrofulaceum M. simiae M. terrae M. immunogenum *Other NTMs are very rare pulmonary pathogens but may present as extrapulmonary pathogens; see ATS guidelines 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) 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 Diagnosis and treatment of lung infection with nontuberculous mycobacteria Arend et al. Current Opinion in Pulmonary Medicine 2009, Nontuberculous Mycobacterial Lung Disease 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 The New NTM ATS Guidelines AJRCCM 175: 367-416, 2007 •Similar diagnostic criteria for MAC and NTM lung disease •3 of 3 criteria required: •History and physical exam - clinical presentation •Chest radiography / Chest CT •Microbiology / histopathology 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 Mycobacterium avium complex lung disease Clinical Presentation • Group 1 : Preexisting lung disease 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 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 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 excavatum • Functional IFN- defects not detected; increased CFTR mutations noted Nontuberculous Mycobacterial Lung Disease 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 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. Nontuberculous Mycobacterial Lung Disease 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 NTM Infection Presentation Common CXR findings: 1 A. Hazy opacity abutting the heart border [#1] Nontuberculous Mycobacterial Lung Disease NTM Infection Presentation Common CXR findings: B. Retrosternal shadowing overlying the cardiac silhouette [#2] 2 Nontuberculous Mycobacterial Lung Disease NTM Infection Presentation Common HRCT scan findings: A.Volume loss and variable [RML] [LING] 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 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 ATS: AJRCCM 175: 367, 2007 Mycobacterium avium complex lung disease Natural History Diagnosis = Treatment ??? Colonization? Infection Disease (treatment) 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 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 Mycobacterium avium complex lung disease Treatment • Overall sputum conversion rates 78% • Previously treated conversion rates 55-64% • Naïve treatment patient conversion 74-92% • Non-cavitary disease 82-92% • 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 Nontuberculous Mycobacterial Lung Disease 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 Clinical Presentations Recap: Symptoms 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 4/13/2011 Nontuberculous Mycobacterial Lung Disease 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 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 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; 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 Mycobacterium avium complex lung disease Treatment •Observation •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: Recent negative inhaled IFN- trial ATS: AJRCCM 175: 367, 2007 Mycobacterium avium complex lung disease Treatment •Surgery •Other contributing factors: Bronchiectasis, GERD, sinus disease •Hot Tub Lung: Ag removal +/- steroids, antimycobacterial Rx ATS: AJRCCM 175: 367, 2007 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? 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 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 Nontuberculous Mycobacterial Lung Disease 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 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 4/13/2011 Nontuberculous Mycobacterial Lung Disease 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 4/13/2011 Nontuberculous Mycobacterial Lung Disease 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. 4/13/2011 Respondent Characteristics Gender Age 38 (83%) women Range: 15-80 8 (17%) men Median: 60 years Race Mean (SD): 59 (11) 45 (98%) White 1 Native American Employment 20 (43%) employed 26 (57%) not employed Onset and Diagnosis Age at onset of Years from symptoms symptoms to diagnosis Range: 3-78 years old Range: 0-30 years Median: 55 Median: 1 Mean (SD): 52 (16) Mean (SD): 4 (6) NTM Medication Use Cycles of therapy Took meds for NTM Range: 0-20 cycles 34 (74%) yes Median: 1 12 (26%) no Mean (SD): 1 (3) Condition in Last 12 Months Culture (22 responses) Symptoms— 13 (59%) Still positive cough, hemoptysis, weight 9 (41%) Converted to loss, loss of appetite, negative fatigue, shortness of breath, fever, depression X-ray (33 responses) (41 responses) 8 (24%) worsened 21 (51%) at least one 25 (76%) not worsened symptom worsened 20 (49%) not worsened Nontuberculous Mycobacterial Lung Disease 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 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 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 Serum IgG Levels in NTM Patients 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 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 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 Questions and Thank you!