1. Slide repository module 4
NTM-LD and COPD
Slide repository module 4
NP-EU

2. Development of the slide repository and financial support
The slide repository was developed by a multidisciplinary European scientific committee:
Stefano Aliberti, Respiratory Physician
University of Milan, Italy
Claire Andrejak, Pulmonologist
CHU Amiens-Picardie, Amiens, France
James Chalmers, Respiratory Physician
Ninewells Hospital, Dundee, UK
Jakko van Ingen, Clinical Microbiologist
Radboud University Medical Centre, Nijmegen, The Netherlands
Gianluca Milanese, Radiologist
University of Parma, Italy
Eva Polverino, Pulmonologist, expert in respiratory infections
Vall d’Hebron University Hospital, Barcelona, Spain
Dirk Wagner, Infectious disease expert
University of Freiburg Medical Centre, Germany
The development of this slide repository by the multidisciplinary European scientific committee was facilitated by Physicians World Europe GmbH and funded by Insmed

3. COPD Epidemiology
COPD is currently cited by the WHO as the third cause of top 10 global causes of death (based on data from 2016) !
COPD claimed 3.0 million lives in 2016 !
Internal Use, Educational Purposes Internally for Discussion only. Permissions requested for owned figures.
COPD, chronic obstructive pulmonary disease; WHO, World Health Organization.

4. COPD – Definition, symptoms, risk factors
Common, preventable and treatable disease
Characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities
Usually caused by significant exposure to noxious particles or gases
Most common respiratory symptoms: dyspnoea, cough and/or sputum production
Frequently associated with significant concomitant chronic diseases, which increase its morbidity and mortality
Main risk factors:
Exogenous factors (e.g. tobacco smoking, biomass fuel exposure, air pollution)
Endogenous factors (e.g. genetic abnormalities, abnormal lung development, accelerated aging)
COPD, chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2018 (

5. History of exposure to risk factors Chronic cough or sputum production
COPD – Diagnosis
Dyspnoea
History of exposure to risk factors
Chronic cough or sputum production
Spirometry required to establish diagnosis (presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation)
Internal Use, Educational Purposes Internally for Discussion only. Permissions requested for owned figures.
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2018 (

6. Smoked regularly and susceptible
Smoking increases the risk of COPD, and smoking cessation can reduce the rate of lung function decline
Never smoked or not
susceptible to smoke
100 75
Smoked regularly and susceptible
to its effects
Stopped
at 45
FEV1 (% of value at age 25) 50
Onset of symptoms
Stopped
at 65
Severe disability 25
Death 25 50 75
Age (years)
Smoking is an important risk factor for the development of COPD symptoms and morbidity
If smoking is stopped early enough, decline in lung function can be delayed
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second. Fletcher C, Peto R. Br Med J 1977; 1:1645-8

7. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017: Symptoms and exacerbation risk should be assessed to determine appropriate treatment
Diagnose COPD and determine the severity of airflow limitation (GOLD Grade 1–4) using spirometry
Determine GOLD Group (A–D) and subsequent appropriate pharmacological treatment by assessing symptoms and exacerbation history (including prior hospitalizations)
Spirometrically confirmed diagnosis
Assessment of airflow limitation
Assessment of symptoms/risk of exacerbations
Exacerbation history
Post-bronchodilator FEV1/FVC < 0.7
Grade
FEV1 (% pred.) 1
≥ 80 2
50–79 3
30–49 4
< 30 C D A B
> 2 or ≥ 1 leading to hospitalization
0 or 1 (not leading to hospital admission)
mMRC 0–1
CAT < 10
CCQ < 1
mMRC 2+
CAT 10+
CCQ 1+
CAT, COPD Assessment Test; CCQ, Clinical COPD Questionnaire; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council. © 2016 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner.

8. A revised approach to treatment recommendations
Group C
Group D
Consider roflumilast if FEV1 < 50% pred. and patient has chronic bronchitis
Consider macrolide
LAMA + LABA
LABA + ICS
Further
exacerbation(s)
LAMA + LABA + ICS
Further
exacerbation(s)
Persistent
symptoms/further
exacerbations
Further
exacerbation(s)
LAMA
LAMA
LAMA + LABA
LABA + ICS
Group A
Group B
Continue, stop or
try alternative class
of bronchodilator
LAMA + LABA
Persistent
symptoms
Evaluate
effect
A long-acting bronchodilator
(LABA or LAMA)
A bronchodilator
FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist. © 2016 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner.

9. COPD – The Current Categories
ACOS1
Bronchiectasis
BCOS2
COPD
Asthma
The most common definition of COPD is that is a combination that does NOT include bronchiectasis but rather patients present with a combination of signs and symptoms of chronic bronchitis, emphysema, and asthma.
(This Venn diagram includes everything from the slide before except bronchiectasis).
Further still, very many clinicians define it as emphysema and chronic bronchitis overlapping only (without asthma). (Purple pointer to asthma).
Internal Use, Educational Purposes Internally for Discussion only. Permissions requested for owned figures.
The presence of COPD and asthma or COPD and bronchiectasis in the same individual may represent new clinical entities1,2
ACOS, asthma-COPD overlap syndrome; BCOS, bronchiectasis COPD overlap syndrome; COPD, chronic obstructive pulmonary disease. 1. Sin DD, et al. Eur Respir J 2016; 48:664-73; 2. Hurst JR, et al. Eur Respir J 2015; 45:310-3.

10. Pathogenesis of chronic lung disease – the Dutch hypothesis
Genetics: Host susceptibility
Airway hyper-responsiveness and inflammation
Environment (e.g. allergens, tobacco smoke)
Chronic non-specific lung disease
Asthma
COPD
Bronchitis
Asthma, COPD and chronic bronchitis may be considered as different forms of chronic non-specific lung disease
COPD, chronic obstructive pulmonary disease. Vestbo J, Prescott E. Thorax 1998; 53 Suppl 2:S15-9.

11. Environmental insult to lungs
COPD Pathogenesis (I)
Genetic susceptibility α1-AT deficiency
Environmental insult to lungs
(long term smoking, pollution, infection)
Decrease in ability of lung to prevent tissue damage
Free radicals produced in the lungs
Inactivation of lung anti-proteases
Internal Use, Educational Purposes Internally for Discussion only. Permissions requested for owned figures.
Lung inflammation
Increase oxidative stress, inflammatory cytokines and protease function
α1-AT, alpha-1 antitrypsin; COPD, chronic obstructive pulmonary disease.

12. COPD Pathogenesis (II)
Lung inflammation
Increase oxidative stress, inflammatory cytokines and protease function
Continued, repeated injury to bronchial tree
Increased proteolytic destruction of lung parenchyma
Chronic bronchitis
Emphysema
Internal Use, Educational Purposes Internally for Discussion only. Permissions requested for owned figures.
COPD
COPD, chronic obstructive pulmonary disease.

13. COPD: Clinical findings
Respiratory signs
Other visible signs
Prolonged expiration
Rapid, shallow breathing
Hoover’s sign
Dyspnoea
Expiratory wheeze
Chronic cough with sputum
Purse-lip breathing
Accessory muscles (e.g. neck muscles) to help breathing
Barrel chest
Fatigue, muscle weakness and wasting
Tripod sitting position
COPD, chronic obstructive pulmonary disease.

14. Prevalence of COPD in patients with NTM-LD50 40 30
% cohort with underlying COPD 20 10
Henkle 20171
Gommans 20152
Andrejak 20133
Winthrop 20104
Huang 20175
Kim
20146
Kumagai 20177
Ide
20158
There is variation between the prevalence of NTM in patients with COPD between countries1–8 (and even within countries1,4)
COPD is the most common underlying lung condition in patients with NTM1–8
Observed across multiple studies affecting between 10–50% of patients with NTM
COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Henkle E, et al. Ann Am Thorac Soc 2017:1120-8; 2. Gommans EP, et al. Respir Med 2015; 109:137-45; 3. Andrejak C, et al. Thorax 2013; 68:256-62; 4. Winthrop KL, et al. Am J Respir Crit Care Med 2010; 5. Huang HL, et al. Sci Rep 2017; 7: :977-82; 6. Kim YK, et al. Int J Tuberc Lung Dis 2014; 18:725-9; 7. Kumagai S, et al. BMC Infect Dis 2017; 17:436; 8. Ide S, et al. PLoS One 2015; 10:e

15. Patients with COPD and NTM-LD are more likely to have fibrocavitary disease80 60
Fibrocavitary disease
% cohort with
underlying COPD
Nodular/bronchiectatic disease 40 20
Zweijpfenning
20171
Koh
20172
Mehta
20113
Fibrocavitary disease is the most common form of NTM-LD, but a significant minority have nodular/bronchiectatic disease1–3
COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Zweijpfenning S, et al. Respir Med 2017; 131:220-4; 2. Koh WJ, et al. Eur Respir J 2017; 50; 3. Mehta M, Marras TK. Respir Med 2011; 105:

16. Andrejak et al: Odds of Developing NTM in various Respiratory Conditions
Exposure
Cases (n=332), n (%)
Population controls (n=3320), n (%)
Unadjusted OR (95% CI)
Adjusted OR* (95% CI)
COPD Absent Present
192 (57.8) 140 (42.2)
3161 (95.2) 159 (4.8)
1.0 (reference) 17.4 (12.8–23.8)
1.0 (reference) 15.7 (11.4–21.5)
First COPD diagnosis
Within 2 years 2–5 years earlier > 5 years earlier
41 (29.3) 39 (27.8) 60 (42.8)
42 (26.4) 30 (18.9) 87 (54.7)
23.4 (13.8–39.7) 18.4 (11.2–30.1) 14.4 (9.6–21.5)
22.5 (13.1–38.5) 16.2 (9.8–26.7) 12.9 (8.6–19.4)
Hospitalised COPD exacerbation
0 within last year
1 within last year
2 within last year
≥ 3 within last year
66 (47.1) 28 (20.0) 12 (8.6) 34 (24.2)
134 (84.2) 12 (7.5) 6 (3.7) 7 (4.4)
7.6 (5.1–11.1) 43.9 (21.9–87.7) 18.3 (5.9–57.0) 65.2 (29.1–146.0)
6.3 (4.2–9.4) 44.0 (21.8–88.9)
17.5 (5.6–54.7) 64.5 (28.5–146.2)
COPD is a leading underlying pathology in those with NTM
*OR adjusted for level of comorbidity and alcoholism-related conditions. CI, confidence interval; COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; OR, odd ratio. Andrejak C, et al. Thorax 2013; 68:

17. Population controls (n=1120)
Andrejak et al: Odds of Developing NTM in patients with COPD according to ICS use
Exposure
Case patients (n=112)
Population controls (n=1120)
Unadjusted OR (95% CI)
Adjusted OR* (95% CI)
Current ICS use (within 6 months), n/N (%)
38/41 (92.7)
26/36 (72.2)
30.4 (15.9–58.0)
29.1 (13.3–63.8)
Low daily use (0–799 μg/day over 1 year)
15/38 (39.4)
15/26 (57.7)
21.9 (9.4–50.7)
28.1 (10.7–73.4)
High daily use (≥ 800 μg/day over 1 year)
7/38 (18.4)
3/26 (11.5)
52.7 (12.1–230.0)
47.5 (9.5–236.7)
The OR for patients with COPD on current ICS therapy was 29.1 for developing NTM
The odds of having NTM increased according to ICS dose from 28.1 for low dose intake to 47.5 for those on a high dose (≥ 800 micrograms/day)
*OR adjusted for level of comorbidity, alcoholism-related conditions, use of oral corticosteroids and other immunosuppressive therapy the year before NTM disease diagnosis, marital status and urbanization of place of residence. CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; NTM, non-tuberculous mycobacteria; OR, odd ratio. Andrejak C, et al. Thorax 2013; 68:

18. Prevalence of concurrent clinically unexpected NTM infection in patients with severe COPD
126 patients undergoing lung volume reduction surgery
Histological examination for evidence of NTM: 142 specimens
Acid-fast bacilli detected 8 (5.6%)
Necrotising granulomas 14 (9.9%)
COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria. Char 2014 BMC Pulm Med

19. NTM isolation is associated with lung function decline in COPD
NTM-LD*
NTM isolation
No NTM isolation
–50
FEV1 decline per year (ml)
–100
–150
Retrospective, single centre study 2000–2008 (N=251)
Significant association between multiple isolates of NTM and FEV1 decline after adjustment for confounders
Patients with multiple NTM isolates also had more exacerbations
*Defined by multiple isolation of NTM. FEV1, forced expiratory volume in 1 second; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. Huang CT, et al. Int J Tuberc Lung Dis 2012; 16:

20. Summary (1)
COPD is currently cited by the WHO as the third cause of top 10 global causes of death (based on data from 2016)1
Common respiratory symptoms include cough, dyspnoea and sputum production2
Concomitant comorbid diseases may lead to increased mortality
Diagnosis is a 3-step process, involving spirometry, assessment of airflow limitation and assessment of risk of exacerbations2
Assessment of exacerbation history can inform treatment plans
The GOLD guidelines are used to help inform diagnosis and treatment options
COPD, bronchiectasis and asthma may all be aspects of a “chronic non-specific lung disease”3
Asthma and bronchiectasis can coexist with COPD, and these overlapping syndromes may be unique clinical entities4,5
COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2018 ( 3. Sluiter HJ, et al. Eur Respir J 1991; 4:479-89; 4. Sin DD, et al. Eur Respir J 2016; 48:664-73; 5. Hurst JR, et al. Eur Respir J 2015; 45:310-3.

21. Summary (2)
COPD is the comorbid condition most frequently observed with NTM-LD1
Fibrocavitary disease is more frequently observed with COPD than nodular/bronchiectatic disease2,3
The odds of having NTM are greater with an increased dose of inhaled corticosteroids1
Patients with NTM-LD and COPD are at greater risk of exacerbations and lung function decline1
COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Andrejak C, et al. Thorax 2013; 68:256-62; 2. Zweijpfenning S, et al. Respir Med 2017; 131:220-4; 3. Mehta M, Marras TK. Respir Med 2011; 105:

22. Glossary
FEV1 Forced expiratory volume in 1 second; the volume of air expelled from the lungs in 1 second when exhaling with maximal effort FVC Forced vital capacity; the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible Hoover’s sign Inward movement of the lower rib cage during inspiration (instead of outward as is normal) implying a flat, but functioning, diaphragm
Purse-lip breathing
Exhaling against pursed lips while inhaling through the nose; keeps airways open longer and reduces the work of breathing
Tripod sitting position
Sitting with the upper body supported with the arms resting on the knees or another surfaces. May optimise the mechanics of respiration by employing accessory muscles of the neck and upper chest, increasing the amount of air reaching the lungs