Nontuberculous Mycobacteria (NTM): Causes of Occupational & Environmental

Lung Disease

Nontuberculous Mycobacteria (NTM): Causes of Occupational & Environmental

Lung Disease

Lee B. Reichman, MD, MPHMeet the Professor

Turkish Thoracic Society

10th Annual Conference

April 25-29, 2007

Kemer, Antalya, Turkey

ObjectivesObjectives

• Overview of spectrum of diseases caused by nontuberculous mycobacteria (NTM).

• Overview of new / emerging NTM.

• Discuss cases of occupational or environmental exposures and NTM disease.

• Briefly review ‘new’ treatment options.

• Discuss research needs.

CaseCase

• 52 y.o. pulp mill worker referred for evaluation of possible underlying occupational lung disease.

• Abnormal chest radiograph and CT.

• VATS biopsy + for AFB and noncaseating granulomas.

• Microbiology: M. avium complex on lung culture.

• Initial exam: Tachypneic. O2 with oximizer at 15 L/min; late inspiratory crackles.

Recovered fully when seen approximately 18 months later.

Spirometry, lung volumes, and diffusing capacity normal.

Mildly increased A-a gradient with maximal exercise.

NTM: Spectrum of DiseaseNTM: Spectrum of Disease

• Pulmonary infections

• Hypersensitivity pneumonitis

• Skin and soft tissue infection

• Lymphadenitis

• Osteoarticular infections

• Disseminated disease

• Nosocomial infections

NTM: Pulmonary Infections -1NTM: Pulmonary Infections -1

• Older men with pre-existing lung disease– COPD, ILD, bronchiectasis, prior TB– Cigarettes, alcohol, s/p gastrectomy, heart dz– Often upper lobe cavities– MAC and M. kansasii most common

• Silico-mycobacteriosis

NTM: Pulmonary Infections -2NTM: Pulmonary Infections -2

• Middle-aged & elderly women– RML and lingular bronchiectasis

• Cystic fibrosis– Rapidly growing mycobacteria

Nontuberculous mycobacteria (NTM)Nomenclature

Nontuberculous mycobacteria (NTM)Nomenclature

• = ‘mycobacteria other than tuberculosis’ (MOTT)

• [disease]= ‘atypical’ tuberculosis

• Most common is M. avium complex – 61% of NTM isolates in U.S.– M. avium and M. intracellulare (MAI)– MAIS = MAI + M. scofulaceum

» O’Brien R et al. ARRD 1987; 135:1007

Other NTM -1Other NTM -1

• Rapidly-growing mycobacteria– 19% of NTM isolates in U.S.

» O’Brien R et al. ARRD 1987; 135:1007

– More than 80% of clinical isolates are

• M. abscessus

• M. chelonae

• M. fortuitum

» Wallace RJ Jr., Clin Chest Med 1989:10:419

Other NTM -2Other NTM -2

• M. kansasii: 10% of US isolates

• Other NTM: remaining 10%

» O’Brien R et al. ARRD 1987; 135:1007

NTM: Diagnosis -1NTM: Diagnosis -1• Compatible symptoms & signs

– Cough, fatigue; wt loss, dyspnea, fever, dyspnea– Exclusion of other diseases, e.g., TB, cancer

• Radiography: CXR or HRCT– Infiltrates (> 2 mo or progressive), nodules, multifocal

bronchiectasis, cavitation

NTM: Diagnosis -2NTM: Diagnosis -2

• Sputum: 3 positive cultures or 2 cxs and 1 smear OR

• Bronchoscopy: single +cx or tissue bx + for AFB with one or more + cx (sputum or BAL)

– Immunocompetent: > 2+ smear or growth– Immunosuppressed: 1+ or greater growth OR

• Extrapulmonary: any + cx

The Older Older Man with MACThe Older Older Man with MAC

Photo courtesy of Michael Iseman, NJRMC

Photo courtesy of Michael Iseman, NJRMC

The Newer Older Woman with MACThe Newer Older Woman with MAC

Hot Tubs and

Aerosol Exposures

Hot Tubs and

Aerosol Exposures:

Co-factors ?

Hot Tub Lung: Indoor >>Outdoor Exposures

Hot Tub Lung: Indoor >>Outdoor Exposures

Hot Tub Lung ReviewHot Tub Lung Review

• Female sex No. (%)

• Mean age, yr (SD)

• Indoor hot tub, No. (%)

• Dyspnea     

• Cough  

• Fever     

• Weight loss

20 (56%)

45 (16)

36 (100%)

35/36 (97%)

28/36 (78%)

21/36 (58%)

8/36 (22%)    

- Marras TK et al. Chest 2005; 127

How It Really HappenedHow It Really Happened

• Family of 5 was quarantined for TB after work-up of wife/mother led to +AFB lung biopsy after 3 months of symptoms.

• Astute public health MD suspected mis-diagnosis based on epidemiology and reviewed CT with colleague at National Jewish. HP was suggested.

• Family members found profoundly ill in home.

– Mangione EJ et al. EIDJ 2001; 7:1039

Showers as a Cause of MAC HP ?Showers as a Cause of MAC HP ?

• 50-year-old male dentist had progressive exertional dyspnea and chest tightness for 3 months with 2-3 self-limited episodes of malaise, subjective fever, and myalgias, each lasting 24 to 72 h.

• HRCT: small, bilateral, diffuse, centrilobular, ground-glass nodules & extensive mosaic attenuation consistent with air trapping on expiratory images

• BAL: 53% lymphocytes.

• Transbronchial biopsies: multiple well-formed nonnecrotizing granulomas, AFB stains negative.

• Microbiology: Cultures from the BAL and two induced-sputa specimens grew MAC.

» Marras TK et al. Chest 2005; 127:664

Environmental StudiesEnvironmental Studies

• Hot tub filtered through swimming pool, both outside. Had not used hot tub for several weeks before symptom onset. Water cultures negative.

• 3 of 4 water specimens from bathtub shower + for MAC. – No air sampling done.

• Near-identical restriction patterns (0-1 band differences) for all respiratory and environmental isolates on pulsed-field gel electrophoresis, suggesting the strains were clonal.

• No specific immunological data.

• Authors concluded exposure must have been from showers.

» Marras TK et al. Chest 2005; 127:664

PFTs in Occupational HPPFTs in Occupational HP

Occupational Hypersensitivity PneumonitisOccupational Hypersensitivity Pneumonitis

• Newly identified NTM species: M. immunogenicum– Shelton BG, Flanders WD, Morris GK. Mycobacterium sp. as a

possible cause of hypersensitivity pneumonitis in machine workers. Emerg Infect Dis 1999; 5:270-273

– Moore JS, Christensen M, Wilson RW, et al. Mycobacterial contamination of metalworking fluids: involvement of a possible new taxon of rapidly growing mycobacteria. Am Ind Hyg Assoc J 2000; 61:205-213

– Respiratory illness in workers exposed to metalworking fluid contaminated with nontubeculous mycobacteria-Ohio, 2001. MMWR Morb Mortal Wkly Rep 2002; 51:349-352

Suggested Approach to Evaluation of Suspected NTM Disease -1

Suggested Approach to Evaluation of Suspected NTM Disease -1

• High index of suspicion- clinical epidemiol– Occupational history: machinist; exposure to metal-

working fluids?– Environmental history: hot tub? Indoor pools?

• Confirm diagnosis with microbiology

Suggested Approach to Evaluation of Suspected NTM Disease -2

Suggested Approach to Evaluation of Suspected NTM Disease -2

• CXR: ALWAYS review all serial films

• HRCT: HP vs. infection

• PFTs: serial FVC and DLCO

• Oxygen needs assessment: desaturation?

NTM Evaluation - 3NTM Evaluation - 3

• Industrial hygiene or environmental scientist consulation: Culture water, fluids and air in home/work. (Best to know your consultant.)

• Communicate with microbiology laboratory: request PGFE or other fingerprinting method

NTM Evaluation - 4NTM Evaluation - 4

• Remove from exposure or remove exposure from patient.

• Treatment: anti-MAC vs. corticosteroids vs. both

Treatment of Pulmonary MAC

Clarithromycin 500 bid or AZI 250 qd

Rifampin 600 or Rifabutin 300 qd

Ethambutol 25 mg/kg x 2 mos., then 15 mg/kg/day

+/- (Streptomycin or) amikacin 2 or 3x/week x 2 months

Treat until culture-negative for 12 months

American Thoracic Society Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease in HIV-Seropositive and HIV-Seronegative Hosts

American Thoracic Society Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease in HIV-Seropositive and HIV-Seronegative Hosts

Criteria DescriptionClinical 1. Symptoms consistent with mycobacterial lung disease; and

2. Radiographic findings (high resolution CT scan): infiltrates, nodular opacities, or cavity disease; or evidence of multifocal bronchiectasis and/or multiple small nodules (ie, tree-in-bud appearance).

Microbiological 1. If three sputum/bronchial wash results are available from the previous 12 mo: three positive culture results with negative AFB smear results; or two positive culture results and one positive AFB smear result; or

2. If only one bronchial wash is available: positive culture with a 2+,3+, or 4+AFB smear, or 2+, 3+, or 4+ growth on solid media; or

3. If sputum/bronchial wash evaluation findings are nondiagnostice or another disease cannot be excluded: transbronchial or lung biopsy yielding NTM; or biopsy specimen showing mycobacterial histopathologic features (ie, granulomatous inflammation and/orAFB) and one or more sputum samples or bronchial washing samples are positive for an NTM even in low numbers.

Comparison of Clinicopathologic Forms of MAC Lung Disease -1

Comparison of Clinicopathologic Forms of MAC Lung Disease -1

Variables Patients with Preexisting

Lung Disease

Immuno-compromised

Patients

Nodular Bronchiec-tasis (Lady

Windermere Syndrome)

Hot Tub

Lung

Age 60-80 yr (except for CF patients)

Younger patients predominate but can occur at any age

55-75 yr Average age, 36 yr (range, 9-69 yr)

Gender Historical male predominance (except in CF patients)

Either Female predominance

Slight female predominance

Presenta-tion

Insidious, often mimics worsening of preexisting disease, more ill on presentation, more smear positivity

May present with or without pulmonary disease, often disseminated

Chronic, evolving over months to years

Subacute, ususally over weeks to months

Comparison of Clinicopathologic Forms of MAC Lung Disease -2

Comparison of Clinicopathologic Forms of MAC Lung Disease -2

Variables Patients with Preexisting

Lung Disease

Immuno-compromised

Patients

Nodular Bronchiec-tasis (Lady

Windermere Syndrome)

Hot Tub

Lung

Radiographic appearance

Bilateral disease, cavitary or fibrocavitary, reticulonodular infiltrates, and consolidation

Bilateral cavitary Nodular infiltrates with cylindrical bronchiectasis, RML and lingular predominance

Diffuse interstitial or nodular infiltrates, ground-glass ocacities and bronchiolitis

Pathologic appearance

Incompletely formed granulomas and caseataing granulomas

Necrotizing granulomas and massive foamy histiocyte proliferation

Granulomatous inflammation with or without necrosis

Discrete nonnecrotiz-ing granulomas

Comparison of Clinicopathologic Forms of MAC Lung Disease -3

Comparison of Clinicopathologic Forms of MAC Lung Disease -3

Variables Patients with Preexisting Lung Disease

Immuno-comprom-

ised Patients

Nodular Bronchiec-tasis (Lady

Windermere Syndrome)

Hot Tub

Lung

Clinical course and treatment

Often chronic, recurrent, or relapsing with less treatment response; treatment of underlying disease key plus bronchial hygiene and therapy with antibiotics

High mortality, even with aggressive antibiotic treatment

Chronic, with reocurrence and relapse; bronchial hygiene and therapy with antibiotics

Responds well to treatment with full recovery after removal from source alone, therapy with antibiotics, and/or with steroids

NTM Pulmonary Disease: Research Needs -1

NTM Pulmonary Disease: Research Needs -1

• Data linking environmental exposures to NTM infection– Suspect indoor exposures more likely than outdoor: higher

concentrations & more frequent.

• Immunological responses to NTM • Markers of disease > exposure

• Markers to distinguish infection & HP ?

• Unusual opportunity in Queensland with Battey ag?

NTM Pulmonary Disease: Research Needs -2

NTM Pulmonary Disease: Research Needs -2

• Risk factors for infection vs. HP– Are exposures really ubiquitous? Or are those affected

exposed more?– If ubiquitous, what are susceptibility factors?

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