This document discusses chronic respiratory disease, inhaled corticosteroids, and the risk of non-tuberculous mycobacteriosis (NTM). It finds that chronic respiratory diseases, especially COPD treated with inhaled corticosteroid therapy, are strong risk factors for NTM pulmonary disease. Among COPD patients, the risk is associated with ICS use, dose, and type, with a higher risk found for fluticasone than budesonide. The pharmacokinetic properties of different ICS, including potency, delivery devices, and pulmonary retention time, influence the risk of pneumonia in COPD patients.

1. Chronic Respiratory Disease,
Inhaled Corticosteroids and Risk of
Non-tuberculous Mycobacteriosis (NTM)
臨藥科技所 碩一 陳秋縈
指導老師 張慧真主任
Feb 6th, 2013

2.  Background
 Chronic respiratory disease and ICS therapy for COPD increase the risk of
pneumonia. Limited data on NTM.
 Objective
 Examine different type of chronic respiratory disease and ICS therapy as risk
factors for NTM pulmonary disease
 Study design
 Population-based case-control study
 Study population
 All adults in Denmark with microbiologically confirmed NTM pulmonary
disease between 1997 and 2008
ICS: inhaled corticosteroids
NTM: Nontuberculous Mycobacteria
Chronic respiratory disease, inhaled corticosteroids and risk of
non-tuberculous mycobacteriosis (NTM)
Thorax. 2012 Jul 10.
ORIGINAL ARTICAL
2

3. Results
 Risk is increased in patient with chronic respiratory disease
 OR for NTM pulmonary disease
Any chronic respiratory disease 16.5 (95% CI 12.2 to 22.2)
− Bronchiectasis 187.5 (95% CI 24.8 to 1417.4)
− Tuberculosis history 178.3 (95% CI 55.4 to 574.3)
− COPD 15.7 (95% CI 11.4 to 21.5)
− Pneumoconiosis 9.8 (95% CI 2.03 to 52.8)
− Asthma 7.8 (95% CI 5.2 to 11.6)
 Among COPD patients, risk is associated with use, dose and type of ICS
 OR for NTM pulmonary disease regard to COPD and ICS use
− Use: concurrent ICS vs. never received ICS 29.1 vs. 7.6
− Dose: low-dose ICS vs. high-dose ICS 28.1 vs. 47.5
− Type: OR was higher for fluticasone than for budesonide 31.0 vs. 19.8
 Conclusion
 Chronic respiratory disease, particularly COPD treated with ICS therapy, is a
strong risk factor for NTM pulmonary disease.
3

4. Inhaled Corticosteroids (ICS) and risk of
pulmonary infection in COPD
4

5. ICS Increase Risk of Pulmonary Infection in COPD
Possible mechanism
 ICS
 Achieve locally high concentrations in the lung which may lead to local
immunosuppressive effects
 COPD
 Persistent inflammation causing airway and mucosal damage
 Compromising local immunity
 Impaired clearance of secretions
 Susceptible patient to high risk of colonization with pathogenic
5

6.  Increased risk of pneumonia associated with3
 Any inhaled corticosteroid (RR 1.57, 95% CI 1.41-1.75, NNH 33-60)
 Fluticasone (RR 1.67, 95% CI 1.47-1.89, NNH 28-53)
 For budesonide
 No significant association with increased risk of pneumonia2,3
 Budesonide/Formoterol reported to have lower risk of pneumonia
than Fluticasone/Salmeterol in patients with COPD 1
 Increased risk of pneumonia is not accompanied by a
corresponding increase in mortality3,4
1. Int J Clin Pract 2011 Jul;65(7):764
2. Lancet 2009 Aug 29;374(9691):712
3. Curr Opin Pulm Med 2010 Mar;16(2):118
4. Arch Intern Med 2009 Feb 9;169(3):219
ICS Increased Risk of Pneumonia in COPD
Literature review
6

7. Risk of Pneumonia Between Different Types of ICS
Possible mechanism
 Potency and dosage
 Effect of delivery devices
− Primary determinants of the dose delivered to the lungs
− ex. Lung delivery of metered-dose inhaler (MDI): 20 %
 Pulmonary retention time
 Removed from the lungs before it substantially downregulates
local immunity and allows proliferation of bacteria
Proc Am Thorac Soc. 2004;1(4):356-63.
Ann Pharmacother. 2009 Mar;43(3):519-27 7

8. Potency and Estimated Comparative Daily Dosages for ICS
Comparative daily dose (mcg)
Drug
Recepter
binding affinity
Low Medium High
Beclomethasone MDI 0.4/13.5 80 -240 240 -480 >480
Budesonide DPI 9.4 200 -600 600 -1200 >1200
Ciclesonide MDI 0.12/12.0 80 -320 320 -640 >640
Flunisolide MDI 1.8 320 320 -640 >640
Fluticasone
MDI
DPI
18 88 -264
100 -300
264 -440
300 -500
>440
>500
Mometasone DPI 23 220 440 >440
Adapted from National Asthma Education and Prevention Program: Expert Panel Report III: Guidelines for the diagnosis and management of
asthma. Bethesda, MD. National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051)
www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on December 6, 2012).
 Potency depends on their receptor-binding affinity
 Potency is the major determinants of the relative comparable
doses
8

9. Risk of Pneumonia Between Different Types of ICS
Possible mechanism
 Potency and dosage
 Effect of delivery devices
− Primary determinants of the dose delivered to the lungs
− ex. Lung delivery of metered-dose inhaler (MDI): 20 %
 Pulmonary retention time
 Removed from the lungs before it substantially downregulates
local immunity and allows proliferation of bacteria
Proc Am Thorac Soc. 2004;1(4):356-63.
Ann Pharmacother. 2009 Mar;43(3):519-27 9

10. Comparison of Delivery Devices
Device Advantages Disadvantages
MDI
Slow deep inhalation
• Portable
• Convenient
• Nonbreath-activated
• Patient coordination essential
• High pharyngeal deposition
• Difficult to deliver high doses
DPI
Rapid deep inhalation
• Portable
• Convenient
• Breath-activated
• Propellant not required
• Difficult to deliver high doses
• High pharyngeal deposition
• Cannot use with endotracheal or
tracheostomy tubes
Nebulizer
• Patient coordination not required
• High doses possible
• Expensive
• Contamination possible
• Device preparation required
MDI: Metered-dose inhaler DPI: Dry powder inhaler
Terbuhaler
Accuhaler
Evohaler
10

11. Risk of Pneumonia Between Different Types of ICS
Possible mechanism
 Potency and dosage
 Effect of delivery devices
− Primary determinants of the dose delivered to the lungs
− ex. Lung delivery of metered-dose inhaler (MDI): 20 %
 Pulmonary retention time
 Removed from the lungs before it substantially downregulates
local immunity and allows proliferation of bacteria
Proc Am Thorac Soc. 2004;1(4):356-63.
Ann Pharmacother. 2009 Mar;43(3):519-27 11

12. Pharmacodynamic/Pharmacokinetic Properties of ICS
Ann Pharmacother. 2009 Mar;43(3):519-27.
Proc Am Thorac Soc. 2004;1(4):356-63.
 Retention of ICS in the lung
 Lipophilicity, Lipid Conjugation
 Distribution into the lipophilic tissues of the lung and slow absorption into
the systemic circulation
Fluticasone is 6 to 8 times more lipophilic than budesonide.
Budesonide is more rapidly cleared from airways than fluticasone.
12

13. 本院吸入性類固醇品項
Drug Device Dose per container Indication Dosage Cost /bot
Budesonide
(Pulmicort Turbuhaler)
200mcg/dose
DPI 100 doses/btl Asthma
Adult: 200-400 mcg bid
Child: 50-200 mcg bid
366
Budesonide
(Duasma)
200mcg/puff
MDI 200 puffs/btl
Asthma Adult: 200-400 mcg bid
Child 6-12 yr: 100-200 mcg bid
394
Budesonide
(Pulmicort Respule)
1mg/2ml/amp
Nebulizer Once Asthma
Adult: 0.5-1 mg bid
Child 6-12 yr: 0.25-0.5 mg bid
67
Fluticasone
(Flixotide Accuhaler)
250mcg/dose
DPI 60dose/btl
Asthma
Adult: 100-1000 mcg bid
250mcg 不適用於兒童
Children: 50-100 mcg bid
545
Salmeterol + Fluticasone
(Seretide Evohaler)
25/50mcg/dose
25/250mcg/dose
MDI 120dose/btl
Asthma
COPD Adult and child≧4 yr: 2puff bid
Adult and child≧12 yr: 2puff bid
819
1433
Salmeterol + Fluticasone
(Seretide Accuhaler)
50/250mcg/dose
DPI 60 doses/btl
Asthma
COPD
Adult and child≧ 4 yr: 1 puff bid 1060
Formoterol + Budesonide
(Symbicort Turbuhaler)
4.5/160mcg/dose
DPI 120dose/btl
Asthma
COPD
Adults & children > 12 yrs, 1-2
doses bid
1257
Beclomethasone + Formoterol
(Foster)
100/6mcg/dose
MDI 120dose/btl Asthma
Adult≧18yr: 1-2 puff bid
需冷藏，拆封後室溫保存可達
5個月
992
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14. Nontuberculous
Mycobacteria (NTM)
 Introduction
 Epidemiology
 Diagnostic criteria
 Treatment
14

15. Nontuberculous Mycobacteria (NTM)
 Mycobacteria other than M. Tuberculosis and M. Leprae
 More than 140 NTM species identified
 One third have been associated with disease in humans
 Environmental organisms found in water and soil
 Not contagious: no evidence of human-to-human
transmission
Am J Respir Crit Care Med. 2007;175:367–416.
Uptodate 15

16. Classification of NTM
 Rapidly growing mycobacteria (RGM)
 M. abscessus, M. chelonae, M. fortuitum
 Slowly growing mycobacteria (SGM)
 Photochromogens
− M. kansasii, M. Marinum, M. Simiae, M. asiaticum
 Scotochromogens
− M. scrofulaceum, M. xenopi, M. szulgai, M. flavscens, M. gordonae
 Nonchromogens
− M. avium complex (MAC), M. Malmoense, M. Ulcerans, M. Terrae complex
Uptodate
16

17. Clinical Manifestation of NTM Disease
 Pulmonary disease (most common )
 Especially in older persons
 M. avium complex (MAC), M. kansasii, M. abscessus
 Probably acquired by aerosol inhalation
 Superficial lymphadenitis
 Especially cervical lymphadenitis
 Children: MAC, M. scrofulaceum
 Skin and soft tissue infection
 Usually as a consequence of direct inoculation
 M. marinum, M. ulcerans, RGM spp
 Disseminated disease
 HIV infection
Am J Respir Crit Care Med. 2007;175:367–416.
17

18. Predisposing factors to NTM lung infection
 Underlying lung disease and altered mucociliary clearance
 COPD, bronchiectasis, cystic fibrosis, pneumoconiosis, previous TB,
esophageal motility disorders
 Immune deficiency
 HIV infection: reduced CD4 T-lymphocyte (usually <100/μL)
 Defects in IFN- γ, IL-12, TNF-α
 Immunosuppressive drugs
 Other underlying conditions
 Malignancy, alcohol abuse
Am J Respir Crit Care Med. 2007;175:367–416.
18

19.  Increased NTM isolation and decreased TB isolation
 From 32.3% to 49.8% (p<0.05)
 Increased disease incidence, predominately pulmonary NTM
disease
 All NTM disease: from 2.7 to 10.2 per 100,000 pt (p<0.0001)
 Pulmonary NTM disease: from 1.26 to 7.94 per 100,000 (p= 0.0194)
Emerg Infect Dis. 2010 Feb;16(2):294-6.
Epidemiologic Trends of NTM in Taiwan
2000-2008
TB
NTM
Prevalence of isolates Incidence of NTM disease
Pulmonary
All
Extrapulmonary
19

20. NTM species causing pulmonary infection in Asia
Distribution of NTM species varies by geographic region
Emerg Infect Dis. 2011 Mar;17(3):343-9.
Taiwan
1. MAC
2. M. abscessus
(RGM)
20

21. Chang Gung Med J. 2009 Sep-Oct;32(5):499-508.
Characteristics of Patients with NTM Pulmonary Diseases
Southern vs. Northern Taiwan
Predominantly male, elderly, pre-existing lung disease.
21

22.  Rapid-growth species and MAC appear to be the major NTM
species in Taiwan
Chang Gung Med J. 2009 Sep-Oct;32(5):499-508.
Pathogens of NTM pulmonary disease
Southern vs. Northern Taiwan
22

23. Symptoms of NTM lung disease
 Variable and not specific symptoms, similar to TB
 Cough (productive or dry)
 Hemoptysis
 Fever
 Night Sweats
 Weight loss and loss of appetite
 Loss of energy
 Others: shortness of breath, wheezing, and chest pain
Am J Respir Crit Care Med. 2007;175:367–416.
23

24. Clinical
 Pulmonary symptoms
 Chest radiograph or chest HRCT scan
 Nodular or cavitary infiltrates, multifocal bronchiectasis
 Exclusion of other diagnoses
 Such as TB, malignancy, fungal disease
Microbiologic
 Recurrent positive culture results from sputum or bronchial wash
 Transbronchial or other lung biopsy with mycobacterial
histopathologic features
 Granulomatous inflammation or AFB
ATS: American Thoracic Society
IDSA: Infectious Disease Society of America's
Am J Respir Crit Care Med. 2007;175:367–416.
ATS/IDSA Diagnostic Criteria for NTM lung disease
Clinical, radiological, and microbiological all required
24

25. Management of NTM Infection
 Empiric therapy not recommended
 Treatment guided by the isolated species
 Species level indentification before proper treatment
 Combination antibiotics
 Susceptibility testing may not correlate to in vivo response in
Slowly growing mycobacteria
 Except
− MAC- macrolide
− M. kansasii- rifampin
 Treatment duration
 Negative culture maintained 1 year on therapy
 Surgery management: localized infections and poor response to
drug therapy
Am J Respir Crit Care Med. 2007;175:367–416.
Curr Opin Pulm Med. 2010 May;16(3):251-6.
Expert Opin Pharmacother. 2012 May;13(7):967-86.
Uptodate 25

26. Treatment of NTM pulmonary disease
Species Preferred regimen
SGM
MAC
Nodular or bronchiectatic: TIW regimen
Clarithromycin 1000mg/ Azithromycin 500-600mg
Rifampin 600mg
Ethambutol 25mg/kg
Fibrocavitary, severe nodular/bronchiectatic: daily regimen
Clarithromycin 500-1000mg/ Azithromycin 250mg
Rifampin 600mg
Ethambutol 15mg/kg
±Amikin/Streptomycin for the first 2 months
M. kansasii
Rifampin 600 mg/day
Isoniazid 300 mg/day
Ethambutol 15 mg/kg/day
RGM
M. abscessus
Clarithromycin 500mg q12h/Azithromycin 200-500mg qd + Amikacin 7.5mg/kg
bid + Cefoxitin 2g q4h/Imipenem 1g q6h
M. fortuitum
M. chelonae
Treatment depend on susceptibility testing
Amikacin, tobramycin,imipenem, cefoxitin, levofloxacin, TMP/SMX,
doxycycline, clarithromycin, azithromycin
Am J Respir Crit Care Med. 2007;175:367–416.
Curr Opin Pulm Med. 2010 May;16(3):251-6.
Expert Opin Pharmacother. 2012 May;13(7):967-86.
Uptodate 26

27. Summary
 Prevalence and incidence of NTM increases
 Patients with underlying diseases with chronic
respiratory disease or immune deficiency are prone to
develop NTM infections
 Clinicians in taiwan should consider NTM as a possible
cause of TB-like disease in these population
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28. Thank you for your attention