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.”
3/14/2016
Nontuberculous Mycobacterial Lung Disease
NTM Pulmonary* Pathogens
Common
Infrequent
M. avium
MAC
}
M. intracellulare
M. xenopi (zin oh’ pee)
M. kansasii
M. malmoense
M. abscessus
(mal’ moh en suh)
M. chelonae (kell oh’ nye)
M. fortuitum
M. szulgai (sull’ guy)
*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
[RML]
[LING]
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
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
3/14/2016
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 nodularbronchiectatic 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. chelonaeabscessus
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
3/14/2016
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
3/14/2016
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.
3/14/2016
Respondent Characteristics
 Gender
 Age
 38 (83%) women
 Range: 15-80

 Median: 60 years
8 (17%) men
 Mean (SD): 59 (11)
 Race
4
1
 20 (43%) employed
3
 Employment
2
1 Native American
FREQUENCY

5
 45 (98%) White
0
 26 (57%) not employed
20
40
60
AGE
80
Onset and Diagnosis
 Years from symptoms
to diagnosis
 Age at onset of
symptoms
 Range: 0-30 years
 Median: 55
 Median: 1
 Mean (SD): 52 (16)
 Mean (SD): 4 (6)
0
10
5
0
1
2
FREQUENCY
3
4
15
 Range: 3-78 years old
0
20
40
60
AGE AT ONSET OF SYMPTOMS
80
0
10
20
YEARS FROM SYMPTOMS TO DIAGNOSIS
30
NTM Medication Use
 Cycles of therapy
 Took meds for NTM
 Range: 0-20 cycles
 Median: 1
 12 (26%) no
 Mean (SD): 1 (3)
0
5
10
15
20
 34 (74%) yes
0
5
10
CYCLES OF THERAPY
15
20
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
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!