Nontuberculous Mycobacteria NTM Old Bug New Threat

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Nontuberculous Mycobacteria NTM Old Bug New Threat Powered By Docstoc
					 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!