Ira Finegold, MDChief of Allergy, St Luke’s-Roosevelt Hospital Center, NYCClinical Professor Medicine, College of Physicians and Surgeons, Columbia University, New YorkPast President ACAAI
Ira Finegold,MD
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
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
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.”
05/03/23
What are the NTMs?
Nontuberculous Mycobacterial Lung Disease
NTM Pulmonary* PathogensNontuberculous 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
NTM Pulmonary* PathogensNontuberculous 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
Mycobacterium avium complex lung diseaseBackground
Not reportable disease - historicallyNot reportable disease - historically 1979-80 : NTM 1/3 of all mycobact isolates1979-80 : NTM 1/3 of all mycobact isolates 1990-91 : NTM 3/4 of all mycobact isolates1990-91 : NTM 3/4 of all mycobact isolates Increased prevalence not well characterizedIncreased prevalence not well characterized Historically, case rate (MAC) estimated Historically, case rate (MAC) estimated
between 0.9 and 4.6 per 100,000 between 0.9 and 4.6 per 100,000 Ontario: ’97-’99 - Ontario: ’97-’99 - 6.36.3/100k to ’01-’03 /100k to ’01-’03
9.39.3/100k/100k( U.S. TB case rate 2004 4.9 / 100,000)( U.S. TB case rate 2004 4.9 / 100,000)
Mycobacterium avium complex lung diseaseBackground
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 mycobacteriaArend et al. Current Opinion in Pulmonary Medicine 2009,
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
The New NTM ATS GuidelinesAJRCCM 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 radiography / Chest CTChest CT
•Microbiology / histopathologyMicrobiology / histopathology
Mycobacterium avium complex lung diseaseClinical 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 diseaseClinical 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
• Group 1 : Preexisting lung diseaseGroup 1 : Preexisting lung disease
Mycobacterium avium complex lung diseaseClinical Presentation
• Group 1 : Preexisting lung disease
Localized or diffuse fibrocavitary disease
Male predominance: smokers
Age: 6th to 8th decade
Mycobacterium avium complex lung diseaseClinical Presentation
• Group 2 : No previous lung disease (Most common)
Mild abnormal pulmonary function tests: obst, Mild abnormal pulmonary function tests: obst, restrictive, mixedrestrictive, mixed
• Associated findings: Associated findings: mitral valve prolapsemitral valve prolapse, , pectus pectus excavatumexcavatum
• Functional IFN-Functional IFN- defects not detected; increased defects not detected; increased CFTR mutations notedCFTR mutations noted
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
Mycobacterium avium complex lung diseaseRadiographic 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.
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 PresentationNontuberculous Mycobacterial Lung Disease
Common CXR findings:
A. Hazy opacity abutting the heart border [#1]
1
Common CXR findings:
B. Retrosternal shadowing overlying the cardiac silhouette [#2]
Nontuberculous Mycobacterial Lung Disease
NTM Infection Presentation
2
NTM Infection Presentation
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]
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, 2007ATS: AJRCCM 175: 367, 2007
Mycobacterium avium complex lung diseaseNatural History
Colonization?Colonization?
InfectionInfection
Disease Disease (treatment)(treatment)
Diagnosis = Treatment ???Diagnosis = Treatment ???
Mycobacterium avium complex lung diseaseNatural 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 diseaseNatural 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 diseaseTreatment
• 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:A725,2000Aksamit,T.R. et al. AJRCCM 161:A725,2000Griffith, D.E. et al. Clin Infect Dis 30:288,2000Griffith, D.E. et al. Clin Infect Dis 30:288,2000Tanaka, E. et al. AJRCCM 160: 866, 1999Tanaka, E. et al. AJRCCM 160: 866, 1999Dautzenberg, B. et al. Chest 107: 1035,1995Dautzenberg, B. et al. Chest 107: 1035,1995
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:
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
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Symptoms
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;
Nontuberculous Mycobacterial Lung Disease
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 diseaseTreatment
•ObservationObservation
•Medical therapyMedical therapy : Triple drug therapy : Triple drug therapyClarithromycin /azithromycin, rifampin/rifabutin , ethambutol Clarithromycin /azithromycin, rifampin/rifabutin , ethambutol +/- streptomycin/amikacin first 2-3months+/- streptomycin/amikacin first 2-3months12 month culture negativity12 month culture negativityRole of quinolones, clofazimine, others ?Role of quinolones, clofazimine, others ?
•Adjunctive therapyAdjunctive therapy::Recent negative inhaled IFN-Recent negative inhaled IFN- trial trial
ATS: AJRCCM 175: 367, 2007ATS: AJRCCM 175: 367, 2007
Mycobacterium avium complex lung diseaseTreatment
•SurgerySurgery
•Other contributing factors:Other contributing factors:Bronchiectasis, GERD, sinus diseaseBronchiectasis, GERD, sinus disease
•Hot Tub LungHot Tub Lung: Ag removal +/- steroids,: Ag removal +/- steroids, antimycobacterial Rxantimycobacterial Rx
ATS: AJRCCM 175: 367, 2007ATS: 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
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
05/03/23
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
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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.
05/03/23
Nontuberculous Mycobacterial Lung Disease
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)
01
23
45
FRE
QU
EN
CY
20 40 60 80
AGE
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)
01
23
4
FRE
QU
EN
CY
0 20 40 60 80
AGE AT ONSET OF SYMPTOMS
05
1015
FRE
QU
EN
CY
0 10 20 30
YEARS FROM SYMPTOMS TO DIAGNOSIS
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)
05
1015
20
0 5 10 15 20
CYCLES OF THERAPY
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
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
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 inthe 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!