Download Danger in the Water

Danger in the Water
Theodore Marras
MD FRCPC
University of Toronto
&
University Health
Network
Declarations
Potential conflicts of interest
Financial – none
Other – clinical and academic interest in
pulmonary NTM disease (especially
epidemiology, long term outcomes)
Off label use of therapies
None of the medications mentioned have a
formal indication for the treatment of
pulmonary NTM disease
Objectives
- Pulmonary Mycobacterium avium complex (pMAC)
1. Identify relevant potential infective exposures
2. Review management of pMAC:
– Recommended drug treatment
– Approach to comprehensive management
3. Review data on treatment outcomes
4. Combining knowledge of:
– Environment / interventions (relevance, uncertainty)
– Treatment outcomes
… to better inform clinical decisions
Background
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Yes
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Yes
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Yes
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Yes
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Micro +
Micro
Yes
Pulmonary NTM
- Microbiology
Where they live
Infection
Spread personperson?
Pathogenic
Diagnosis
NTM
M.tb.
Environment
(water, soil)
Environmental
exposure /
inoculation
No
Infected
host
Infective
aerosols
Weakly
Strongly
Micro / Clin / Rad
Micro
Yes
Pulmonary NTM Disease
- ATS / IDSA 2007
“Disease” Criteria
Clinical Pulmonary symptoms, or
Nodules or cavities on CXR, or
Multifocal bronchiectasis & multiple small
nodules on HRCT
(and exclusion of other diagnoses)
Micro
With > 2 sputa  2 cultures +
With 1 BAL/wash  1 BAL/wash +
With biopsy 
• 1 biopsy culture +, or
• 1 culture + and bx evidence of disease
Age and sex distribution
Prevalence of pulmonary MAC disease by age and gender,
Ontario 2008
45
40
35
per 100,000
30
25
2008 Male
20
2008 Female
15
10
5
0
<50
50-69
Age group
≥70
Increasingly common disease of the elderly
in Ontario
Where does it come from?
The Water we Drink
- MAC
• Moist environments
– Natural and treated water
– Soils
• Very disinfectant resistant
Hot Tub Lung:
Hypersensitivity Pneumonitis to NTM
•Embil et al.
Chest 1997
5
•Kahana et al.
Chest 1997
1
•Mangione et al.
Emerg Inf Dis 2001
5
•Case record
NEJM 2000
1
•Khoor et al.
Am J Clin Pathol 2001
•Rickman et al.
Mayo Clin Proc 2002
2
•Cappelluti et al.
Arch Intern Med 2003
1
•Pham et al.
J Thoracic Imaging 2003
1
•Grimes et al.
Respiration 2001
1
•Aksamit
Respir Infect 2003
9
•Lumb et al.
Appl Environ Micro 2004
4
•Systrom & Wittram
NEJM 2005
1
TOTAL
10
41
Pulmonary NTM
Source of infection
Study Design
Hypersensitivity Pneumonitis
Reaction to Mycobacterium avium
in Household Water*
Theodore K. Marras, MD; Richard J. Wallace, Jr., MD, FCCP; Laura L.
Koth, MD; Michael S. Stulbarg, MD;† Clayton T. Cowl, MD, FCCP; and
Charles L. Daley, MD
… Multiple respiratory samples and shower and bathtub
specimens grew MAC, with matching PFGE patterns…
(CHEST 2005; 127:664–671)
Pulmonary NTM
Source of infection
Mycobacterium avium in a shower linked to pulmonary
disease
Joseph O. Falkinham III, Michael D. Iseman, Petra de Haas and Dick van Soolingen
… M. avium isolated from showerhead water and biofilm in the
home of a woman with M. avium disease. DNA fingerprinting
demonstrated identical M. avium isolates from showerhead and
patient …
J Water Health 06(2):209–213
MAC skin testing
- Soil exposure
Study Design
Occupational soil exposure - risk factor
for MAC skin test reactivity
MAC skin testing
- Soil exposure
Study Design
Occupational soil exposure - risk factor
for MAC skin test reactivity
Study
Population
Risk Factor
Reed
Am J Epi 2006
Random sample, West
Palm Beach FL (N=447)
Soil occupation
(> 6 years)
Khan
AJRCCM 2007
Representative sample,
USA (N=7,384)
Farming /
Construction
Odds Ratio
(95% CI)
P
value
2.7
(1.3-6.0)
0.01
1.43
(1.07-1.92)
0.02
MAC skin testing
- Soil exposure
Study Design
Occupational soil exposure - risk factor
for MAC skin test reactivity
Study
Population
Risk Factor
Reed
Am J Epi 2006
Random sample, West
Palm Beach FL (N=447)
Soil occupation
(> 6 years)
Khan
AJRCCM 2007
Representative sample,
USA (N=7,384)
Farming /
Construction
Odds Ratio
(95% CI)
P
value
2.7
(1.3-6.0)
0.01
1.43
(1.07-1.92)
0.02
MAC skin testing
- Soil exposure
Study Design
Occupational soil exposure - risk factor
for MAC skin test reactivity
Study
Population
Risk Factor
Reed
Am J Epi 2006
Random sample, West
Palm Beach FL (N=447)
Soil occupation
(> 6 years)
Khan
AJRCCM 2007
Representative sample,
USA (N=7,384)
Farming /
Construction
Odds Ratio
(95% CI)
P
value
2.7
(1.3-6.0)
0.01
1.43
(1.07-1.92)
0.02
Pulmonary NTM
Source of infection
High numbers of … M. avium, M. intracellulare, and M. chelonae,
recovered from aerosols produced by pouring commercial potting soil
and potting soil samples provided by patients with pulmonary
mycobacterial infections.
Dominant mycobacteria in soil samples corresponded to dominant
species implicated clinically. Pulsed-field gel electrophoresis
demonstrated a closely related pair of M. avium isolates recovered
from a patient and from that patient’s own potting soil.
App Env Microbiol 2006; 72:7602-6.
Management of pMAC
ATS / IDSA guidelines
- Diagnosis  Treatment
Symptoms + Imaging + Cultures
= NTM Disease
“Making the diagnosis of NTM lung disease does not,
per se, necessitate the institution of therapy, which
is a decision based on potential risks and benefits of
therapy for individual patients”
- ATS / IDSA 2007
ATS / IDSA guidelines
- Diagnosis  Treatment
Symptoms + Imaging + Cultures
= NTM Disease
“Making the diagnosis of NTM lung disease does not,
per se, necessitate the institution of therapy, which
is a decision based on potential risks and benefits of
therapy for individual patients”
- ATS / IDSA 2007
Pulmonary NTM
- Diagnosis  Treatment
When to treat?
Micro
– Repeated isolates / AFB smear +
Symptoms
– Systemic* – fatigue, fever/sweat, weight loss
– Local – cough, sputum, hemoptysis, dyspnea
Significant burden on imaging
– Consolidation, nodules, cavities …
– Progression
Pulmonary MAC
- Goals of treatment
Non-destructive infection
• Cure
Localized destruction
• Cure (?)
Diffuse destruction
• Suppress
Severe drug intolerance
• Suppress
Recurrence
• Cure or Suppress?
Pulmonary MAC
- Goals of treatment
Non-destructive infection
• Cure
Localized destruction
• Cure (?)
Diffuse destruction
• Suppress
Severe drug intolerance
• Suppress
Recurrence
• Cure or Suppress?
Pulmonary MAC
- Goals of treatment
Non-destructive infection
• Cure
Localized destruction
• Cure (?)
Diffuse destruction
• Suppress
Severe drug intolerance
• Suppress
Recurrence
• Cure or Suppress?
Pulmonary MAC
- Goals of treatment
Non-destructive infection
• Cure
Localized destruction
• Cure (?)
Diffuse destruction
• Suppress
Severe drug intolerance
• Suppress
Recurrence
• Cure or Suppress?
Pulmonary MAC
- Goals of treatment
Non-destructive infection
• Cure
Localized destruction
• Cure (?)
Diffuse destruction
• Suppress
Severe drug intolerance
• Suppress
Recurrence
• Cure or Suppress?
ATS / IDSA guidelines
- Drug treatment – MAC
Drug / class
Disease type
Fibronodular
Cavitary or Advanced / recurrent
MACROLIDE
Clari 1000 tiw or
Azi 500-600 tiw
Clari 500-1000 qd
or
Azi 250-300 qd
Ethambutol
20-25 mg/kg tiw
15 mg/kg/d
RMP 600 tiw
RMP 450-600 qd
or
RFB 150-300 qd
Rifamycin
Amikacin
(SM, KM)
Not recommended
Consider / recommended
(10-15 mg/kg/d)
ATS / IDSA guidelines
- Drug treatment – MAC
Drug / class
Disease type
Fibronodular
Cavitary or Advanced / recurrent
MACROLIDE
Clari 1000 tiw or
Azi 500-600 tiw
Clari 500-1000 qd
or
Azi 250-300 qd
Ethambutol
20-25 mg/kg tiw
15 mg/kg/d
RMP 600 tiw
RMP 450-600 qd
or
RFB 150-300 qd
Rifamycin
Amikacin
(SM, KM)
Not recommended
Consider / recommended
(10-15 mg/kg/d)
Other agents - Fluoroquinolones, clofazimine, linezolid
Pulmonary NTM
- Treatment duration
When to stop?
Sputum cultures negative for 12 months
Comprehensive
management
Pulmonary MAC
- Drugs
•
•
•
•
•
Start with guidelines
Expect drug intolerance (staggered start)
Macrolides whenever possible
Amikacin for advanced cases*
Fluoroquinolones, clofazimine, linezolid as needed /
tolerated
• Aim for >3 drugs*
– More drugs, higher doses  greater efficacy
• Tailor therapy
– Switch drugs to minimize AE’s
– Re-evaluate objectives based on response, toxicity
* When treating intensively
Pulmonary MAC
- Treatment – Other
Other interventions
• Nutrition
• Bronchodilators /
Inhaled steroids?
• Pulmonary hygiene
• Surgery
• Avoid exposure
– Hot tubs
– Shower?
Pulmonary MAC
- Treatment – Other
Other interventions
• Nutrition
• Bronchodilators /
Inhaled steroids?
• Pulmonary hygiene
• Surgery
• Avoid exposure
– Hot tubs
– Shower?
Pulmonary MAC
- Treatment – Other
Other interventions
• Nutrition
• Bronchodilators /
Inhaled steroids?
• Pulmonary hygiene
• Surgery
• Avoid exposure
– Hot tubs
– Shower?
Pulmonary MAC
- Treatment – Other
Other interventions
• Nutrition
• Bronchodilators /
Inhaled steroids?
• Pulmonary hygiene
• Surgery (?)
Pulmonary MAC
- Following patients on therapy
Assess response
Microbiologic – sputum q 2-4 months
Clinical – periodic
Radiographic – LDCT scan 4-6 mo, then q 6-12 mo
Follow for drug toxicities
•
•
•
•
•
Education  important toxicity stop drugs
Clinical
Rifamycin  CBC, liver tests
Ethambutol  visual acuity, colour etc.
Amikacin  ‘lytes, creatinine, serum level, audiograms
Outcomes
pNTM – a chronic disease?
- Clinical practice
Clinical practice (geographic region)
• Leeds, UK; MAC 1999-2001
• 41% disease recurrence or mortality
at 2 years post treatment
Henry, ERJ 2004
pNTM – a chronic disease?
- Clinical practice
Clinical practice (specialty clinic)
• 50% didn’t achieve sputum culture
conversion
• 60% didn’t tolerate initial antibiotics
• 85% remain symptomatic
Huang, Chest 1999
pNTM – a chronic disease?
Study
- Clinical studies
Rx
(months)
N
Dautzenberg ’95
Wallace ’96
Roussel ‘98
Griffith ’98
Tanaka ’99
Huang ’99
Griffith ‘00
Griffith ‘01
Field ’02
Kobashi ‘03
12
>5
15
>6
6
>12
>6
12
>5
12
39
48
29
68
46
27
59
103
30
71
Fujikane ’05
Lam ’06
Kobashi ’07
Kobashi ’07
>6
12
24
24
137
91
73
146
97
21
57
61
79
13
51
61
82
83
14
18
66
53
12
18
Jenkins ’08
24
170
90
90
33
33
-
1,137
72%
62%
50%
43%
Total (weighted)
Sputum convert (%)
PP
ITT
77
65
97
75
67
48
66
56
72
61
71
37
78
54
61
54
100
87
58
58
Success (%)
PP
ITT
77
65
86
67
57
41
66
56
63
48
36
19
78
54
61
54
81
70
32
32
pNTM – a chronic disease?
- Recurrence
Study
Huang ’99
Kobashi ’07
Kobashi ’07
Total (weighted)
Follow-up
(months)
<72
36-48
36
-
N
27
73
146
246
Recurrence
N
%
3/10
30
21/37
57
29/89
33
53/136 39%
Pulmonary MAC (NTM)
- Chronicity
Treatment
– Poorly tolerated
– Suboptimal efficacy
Pulmonary MAC (NTM)
- Chronicity
Treatment
– Poorly tolerated
– Suboptimal efficacy
Cause(s) not identified or reversible
– Host defect
– Exposure remains…
Am J Resp Crit Care Med 2007, 175:367-416
Canadian Tuberculosis Standards, 6th ed
www.ntminfo.org