Comorbidities in COPD

1. By
Mohamed Elnady
Prof. Of Chest Diseases
Director of chest unit
New Kasr Al-Aini Teaching Hospital
Cairo University
hakimnady@hotmail.com
Comorbidities in COPD

3. New Kasr Al-Aini Teaching Hospital
French Hospital

4. Contents
• Definition.
• Introduction.
• Exposome & Spill over.
• Comorbidities: (CV, Pulmonary,
Osteoporosis, DM, MS,
Obesity, Cachexia, GERD,
Skeletal muscle, Depression ,
Anxiety & Aging)
• Mangement.
• One size does not fit all.

5. Co-morbidity relationship exists
between two diseases whenever
they affect the same individual
substantially more than chance
alone.
Hidalgo et al PLoS Comput Biol 5(4):2009
Definitions

6. Assessing Co morbidities in COPD
Agusti A and Jardim J, personal communication.
Look for
Look for
COPD Comorbidities
If Smoker
COPD forum, A. Agusti

8. Antonio Anzueto, MD: We need to look at
the individual, not look at the disease

9. Byron Thomashow, MD: You need to treat the
person with COPD, not the COPD

10. Byron Thomashow, MD: We know very little about how
COPD actually behaves in the nonsmoking population

11. Genome
Environment
Modified from Loscalzo et al Mol Sys Bio 2007;3:124

12. Genome ( DNA)
Transcriptome (RNA)
(gene expression)
Proteome
(Large molecules) (protein expression)
Environment
Inflammation
Thrombosis
Hemorrhage
Fibrosis
Immune
response
Apoptosis
Necrosis
Cell
proliferation
Abnormal organ function
Disease with different phenotypes
Modified from Loscalzo et al Mol Sys Bio 2007;3:124
Metabolome
EXPOsOMICS
Discovering Environmental Causes of Disease: from
Exposure Biology to the Exposome
(Small molecules)

13. Exposome
‘everything except the genes’

15. 0
20
40
60
80
100
120
140
160
180
200
GOLD 2001
mention comorbidities
(5 lines)
Number of publications containing the terms
“COPD AND Comorbidities”
PubMed accessed Sept. 2015 @ http://www.ncbi.nlm.nih.gov/pubmed/
GOLD 2006
mention comorbidities
(Chapter 6 full paragraph)
GOLD 2011
Comorbidities take center stage
with a dedicated chapter

16. 16
Cardiovascular
disease
Lung cancer
Anxiety,
depression
Osteoporosis
Cachexia
Gastrointestinal
complications
Diabetes
Metabolic syndrome
Systemic comorbidities in COPD
• Adapted from Kao C, Hanania NA.
• Co-morbidities of COPD-Systemic Inflammation. Atlas of COPD 2009

19. 19

23. Wayne McLaren…Former Marlboro Man
Age 30…a robust
young man
Age 51…riding
into the sunset

24. McMullan and Cohen, N Engl J Med 2006; 354:397
COPD: Local, systemic or multi disease?

25. Lung
Cancer
Anxiety*
Breast Cancer*
CAD
A. Fibrillation
CHF
OSA
Pulmonary
HTN/RHF
Pulmonary Fibrosis
BPH
CRF
Diabetes w/
Neuropathy
Diabetes
Erectile
Dysfunction
Gastric
Duodenal
Ulcer
Liver
Cirrhosis
Esophageal
CancerPancreatic
Cancer
Hypertension
PAD
CVA
Hyperlipidemia
Substance
Abuse
DJD
Depression
GERD
Prevalence
Risk
1/HR=0.5
50%
10%
Death
The Comorbidome
Divo et al, AJRCCM 2012

27. Increased Risk for Cardiovascular Disease
in COPD
MI = myocardial infarction, CHF = congestive heart failure, CVD = cardiovascular disease;
All between-group differences P < 0.05 – adjusted for CV risk
Curkendall SM, et al. Ann Epidemiol. 2006;16:63-70.
21.1
11.2
5.6
31.3
9.6
70.4
22.8
11.7
6.4
3.2
9 7.9
54
11.2
0
10
20
30
40
50
60
70
80
Arrhythmia Angina Acute MI CHF Stroke Other CVD CVD
Hospitalization
PercentofSubjects
COPD (N = 11,493)
Controls (N = 22,986)

28. Tamagawa E et al. Chest. 2006;130:1631-1633.
Lung Inflammation and Vascular Disease
Effects of Lung Inflammation on Blood Vessels

29. Iwamoto et al AJRCCM 2009 ;179: 35
Airflow limitation in smokers is associated
with subclinical atherosclerosis
Meancarotidintimalthickness(mm)
Percentageofcarotidplaque

31. Inflammatory Processes and Anaemia
Proinflammatory
cytokines
ReactiveO2
composition
Erythrocytes
Dyserythropoiesis
Erythrophagocytosis
IFN-
IL-1
TNF
1-antitrypsin
Shortened survival Impaired iron usage Suppressed BFU-E/CFU-E Reduced EPO-production
IFN-
IL-1
TNF
↓HIF-1
IFN-,β
IL-1
TNF
Activated immune system
Macrophages
TNF
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Clinical Oncology,
www.nature.com/clinicalpractice/onc (Bohlius J, et al. Nat Clin Pract Oncol. 2006;3:152-164), copyright 2006.

32. Anaemia and Mortality in COPD
262
133
0
50
100
150
200
250
300
COPD with Anaemia COPD without Anaemia
Deathsper1,000Patient-years
Halpern MT, et al. Cost Effect Res Allocation. 2006;4:17-24.
P<0.001

33. Inverse relationship between degree of lung function
obstruction and incidence of lung cancer
Mannino et al Arch Intern Med 2003; 163: 1475

34. The last Marlboro Man, Wayne McLaren,
who died of lung and brain cancer

35. 10
47
11
79
27
123
86
215
0
50
100
150
200
250
URTI (n=1,411) LRTI (n=312)
Normal Mild Moderate Severe to very severe
No.infectionsper10,000patient-years
COPD severity:
Increased hospitalization risk for infection with advancing
COPD severity, for both URTI and LRTI (p=0.0001)
Pulmonary infections are frequent in patients with
COPD and hospitalization risk increases with disease severity
URTI = upper respiratory tract infection;
LRTI = lower respiratory tract infection Benfield T, et al. Chest 2008

36. Antonio Anzueto, MD: COPD with dental disease have more
exacerbations. I’m the only one in the clinic that uses
tongue depressors. Nobody uses tongue depressors. I look in
everybody’s mouth.

37. Co-existence of asthma and COPD increases the
likelihood of frequent and severe exacerbations
*p<0.0001 for the difference
between COPD and COPD with asthma Hardin M, et al. Respir Res 2011
COPD
(n=796)
COPD
(n=796)
COPD and
asthma
(n=119)
COPD and
asthma
(n=119)
18.0%
42.7%*
17.6%
32.8%*
0
10
20
30
40
50
0
10
20
30
40
50
Patients(%)
Patients(%)
Frequent exacerbations Severe exacerbations
• 119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma

38. 1.0
0.4
0.9
0.8
0.7
0.6
0.5
Follow-up (months)
0 20 40 60 80 100
Cumulativesurvival
COPD without bronchiectasis
(n=86; 8 deaths)
COPD with bronchiectasis
(n=115; 43 deaths)
Bronchiectasis is associated with an increased risk of
mortality in patients with moderate-to-severe COPD
• The prevalence of
bronchiectasis is increased
in patients with moderate-
to-severe COPD and is
associated with severe
airflow obstruction and
hospital admission for
exacerbation1
• The risk of all-cause
mortality in patients with
moderate-to-severe COPD
is also increased with
bronchiectasis2
1. Martínez-García MA, et al. Chest 2011
2. Martínez-García MA, et al. Am J Respir Crit Care Med 2013

39. COMBINED PULMONARY FIBROSIS
EMPHYSEMA SYNDROME

40. 18 months 12 months~5 years
Emphysema
Fibrosis
PH
Cancer
7 months

41. Management of patients with CPFE
• No specific treatment for CPFE.
• Smoking cessation; bronchodilators; supportive care;
oxygen supplementation; lung transplant
• Anti-fibrotic therapy (pirfenidone, nintedanib): little
evidence in CPFE
• Discuss corticosteroids ± azathioprine if NSIP considered
• Patients with severe precapillary PH due to lung diseases
should be enrolled in RCTs targeting PAH-specific drugs1;
avoid ambrisentan (ARTEMIS)
Sieger W et al, J Am Coll Cardiol 2013

42. Normal bone Osteoporosis
A disease characterised by low bone mass and
microarchitectural deterioration of bone tissue leading to
enhanced bone fragility and a consequent increase in
fracture risk.
Osteoporosis

43. ➢ Prevalence of Osteoporosis increased in
COPD Related to:
1. Smoking
2. Corticosteriods
3. Malnutrition – Vit D deficiency
4. Sedenterism
5. Hypogonadism
6. Systemic Inflammation
Incalzi et al Resp Med 2000:94:1079, Biskobing et al Chest 2002;94:609,
Ionescu et al ERJ 2003;22:Suppl 46:64s
Osteoporosis

44. Severe Obstructive Airway Disease Is
Associated With Greater Risk of Fracture
de Vries F, et al. Eur Respir J. 2005;25:879-884.
0.2 0.5 1 2.0 5.0
Hip fracture
Osteoporotic fracture
Vertebral fracture
*Adjusted in patients with severe COPD for general risk
factors, smoking status, duration of enrollment, and
exposure to bronchodilators
ICS - No
ICS - Yes
ICS - No
ICS - Yes
ICS - No
ICS - Yes
Odds Ratio*

45. 0.0
0.2
0.4
0.6
0.8
1.0
COPD (n=2,505) No COPD (n=726,840)
GOLD
group
Diabetes (%)
CAT score mMRC score
A 4.1 13.0
B 15.8 15.8
C 0 18.7
D 28.5 32.3
Chi-squared 42.0 43.3
p-value <0.001 <0.001
COPD symptoms assessed
by CAT and mMRC scoreMultivariate RR 1.8
(95% CI 1.1, 2.8)
Risk and incidence of diabetes are increased in
patients with COPD
• A cohort study of female nurses found that
the risk of type 2 diabetes was
significantly higher for those with COPD
than those without1
CAT = COPD Assessment Test;
mMRC = modified Medical Research Council;
RR = rate ratio
1. Rana JS, et al. Diabetes Care 2004
2. Jones PW, et al. Respir Med 2014
Percentofsubjectswithincidentdiabetes
• In an analysis of 1,041 patients with
COPD classified using the GOLD
recommendations, the incidence of
diabetes was higher in GOLD Group D
than in Groups A and B2

46. 47%
21%
Prevalence of metabolic syndrome appears
to be a frequent occurrence in patients with COPD
†Metabolic syndrome 3 of the following: abdominal
obesity, elevated triglycerides, reduced high-density
lipoprotein cholesterol, hypertension, hyperglycemia Marquis K, et al. J Cardiopulm Rehabil 2005
0
10
20
30
40
50
COPD (n=38) No COPD (n=34)
Patientswithmetabolicsyndrome†(%)

47. Both obesity and cachexia are common
comorbidities in patients with COPD
• Obesity is more common in those with COPD
than in the general population.1
• However, fat-free mass may also be reduced in
patients with COPD2
– Approximately 25% of patients with COPD will develop
cachexia
– Cachexia in patients with COPD is associated with a
reduction in median survival of ~50%
1. Franssen FME, et al. Thorax 2008
2. Wagner PD. Eur Respir J 2008

48. CHRONIC BRONCHITISEMPHYSEMA
BLUE BLOTTERPINK PUFFER

49. Risk factors for IPF have been
identified
1. Baumgartner KB, et al. Am J Respir Crit Care Med 1997;155:242–248; 2. Ryu JH, et al. Eur Respir J 2001;17:122–132;
3.; Ley B, Collard HR. Clin Epidemiol 2013:5:483–492; 4. Molyneaux P, Maher T. Eur Respir Rev 2013;22:376–38; 5.
Raghu G, et al. Eur Respir J 2006;27:136–142; 6. Tobin RW, et al. Am J Respir Crit Care Med 1998;158:1804–1806; 7.
Bandeira CD, et al. J Bras Pneumol 2009;35:1182–1189; 8. Salvioli B, et al. Digest Liver Dis 2006;38:879–884; 9. Gao F, et
al. BMC Gastroenterol 2015;15:26.
Cigarette smoking
• History of smoking strongly
associated with an increased
risk of IPF (OR 1.6–2.3)1
• 41–83% of IPF patients are
current of former smokers2*
Environmental pollutants
• Exposure to metal and wood
dusts, farming, raising birds,
hairdressing and stone cutting/
polishing, associated with an
increased risk of IPF3
Environmental factors
• Proposed cause of repeated
micro-injury
• Estimated prevalence of GERD
in IPF: 35.7–94%5–9
GERD
Infection
• Herpes viruses and
hepatitis C virus linked to
the pathogenesis,
progression and
exacerbation of IPF4
Genetic factors
• Familial pulmonary fibrosis
accounts for < 5% of total
population with IPF3
• Mutations in telomerase genes
(TERT, TERC), surfactant
proteins gene (SPC, SPA2),
mucin 5B (MUC5B), ELMOD2
and TOLLIP 3

50. Outcome Odds ratio (95% CI)
SGRQ total score 3.38 (1.86, 4.90)
Frequent exacerbator during follow-up
(≥2 exacerbations per year)
1.40 (1.10, 1.79)
GERD is associated with worse outcomes in
COPD patients
GERD = gastroesophageal reflux disease;
SGRQ = St George’s Respiratory Questionnaire Martinez C, et al. Respir Res 2014
• Among 4,483 participants of the COPD Gene study with COPD of any GOLD
stage, physician-diagnosed GERD was reported by 29.1% of subjects, more
frequently among women and older individuals
• The presence of GERD was associated with worse health status and more
frequent exacerbations during follow-up

51. Major comorbidities in COPD
Skeletal muscle
dysfunction

52. Which of these
COPD patients has
A systemic disease ?
Answer: BOTH
From T Petty
Treatment should be
directed to the
systemic effects of
COPD

53. Peripheral muscle weakness in COPD
Bernard S et al. AJRCCM 1998; 158: 629
80
60
40
20
0
Strength(kg)
Quadriceps Pectoralis Latissimus
major dorsi
Normal
COPD
FEV1 42±14% pred
*
*
100

54. Quadriceps strength predicts mortality in
patients with moderate to severe COPD
Swallow et al. Thorax 2007;62:115

56. Prevalence of depression and anxiety are both
increased in COPD
*p<0.05; **p<0.01 for the difference
between COPD and no COPD De Miguel Díez J, et al. Respirology 2011
15.9% 15.6%
7.6%
9.4%
0
2
4
6
8
10
12
14
16
18
Depression Anxiety
COPD (n=1,320) No COPD (n=18,740)
Patientswithcomorbidity(%)
* **

57. Anxiety and depression are associated with
poorer outcomes in COPD
• Anxiety and/or depression associated with:
– Reduced exercise performance1
– Increased dyspnea1
– Reduced quality of life1,2
– Higher BODE index1
• Anxiety associated with:
– Reduced exercise performance3,4
– Increased dyspnea4
– Reduced quality of life4
– Increased COPD exacerbations3
– Increased self-reported functional limitations3
BODE = body mass index, degree of airflow obstruction,
dyspnea and exercise capacity
1. An L, et al. Chin Med J (Engl) 2010
2. Balcells E, et al. Health Qual Life Outcomes 2010
3. Eisner MD, et al. Thorax 2010
4. Giardino ND, et al. Respir Res 2010
➢Pulmonary
rehabilitation.
➢Smoking cessation.
➢ Psychological and
antidepressants drug
therapy

58. Systemic Effects of COPD:
Target Organs
Lung Infections
Lung Cancer
Weight loss
Muscle weakness
Osteoporosis
Angina
Acute coronary
syndromes
Diabetes
Metabolic syndrome
Peptic ulceration
Depression
Systemic
Inflammation
Oxidatitive Stress Depression
ACCELERATED AGING

59. Accelerated aging (Telomere shortening) in COPD
Telomeres cap the ends of chromosomes protecting
them from degradation and fusion.
Undergo erosion with each cycle of replication enhanced
by oxidative stress.
Marker of oxidative stress and biological ageing.

62. Treatment of COPD
comorbidities

63. 0
10
20
30
40
50
60
HTN
CAD+MI
Degenerativejointdisease
GERD
Deppresion
CHF
AF+Flutter
Erectiledysfunction
Emphysema
PulHTN+CP
Prostatecancer
Osteoporosis
Breastcancer
Pulmonaryfibrosis
DVT
Otherarrythmia
Gout
NeurophatyDM
Hepatitis
Nephrolithiasis
ConnectiveTissuedisorders
Dementia
Livercirrhosis
Bronchiectasis
Pancreatitis
Coloncancer
Restlesslegsyndrome
Melanoma
MAI
Parkinson
InflamatoryBoweldisease
Kidneycancer
Livercancer
Braincancer
Thyroidcancer
HIV
Testiculacancer
Rectalcancer
BOOP
Celiacdisease
Prevalence (%) n=1659 Patients
Assessment= anamnesis
Setting=Multicenter – outpatient
Follow up= Mean 4.5 years
79 comorbidities
BODE Cohort: Comorbidity prevalence
Divo et al AJRCCM 2012

65. PERSONALIZED
TREATMENT of COPD

66. 66

67. Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic
Patient
Group
Essential Recommended Depending on local
guidelines
A
Smoking cessation (can
include pharmacologic
treatment)
Physical activity
Flu vaccination
Pneumococcal
vaccination
B, C, D
Smoking cessation (can
include pharmacologic
treatment)
Pulmonary rehabilitation
Physical activity
Flu vaccination
Pneumococcal
vaccination
© 2015 Global Initiative for Chronic Obstructive Lung Disease

68. Smoking cessation
it’s never too late……

71. Central desensitization
to dyspnea
Reduction in dynamic
hyperinflation
Decreased anxiety and depression
Improved skeletal-muscle function

72. •Rising from a chair, lifting weights
and maintaining balance on one
foot are all examples of strength
training.
•Strength + endurance training in
COPD patients leads to increasing
muscle mass.
Casaburi R. Getting Serious About Strength
Training. Journal of Cardiopulmonary
Rehabilitation; 2006(26).

74. Pursed lip breathing is by far the
most useful tool that our patients
report having learned!

75. Pursed-Lip Breathing
• Increases ventilation
• Releases trapped air in lungs
• Keeps airways open longer (WOB)
• Prolongs exhalation – slows breathing
• Improves breathing patterns - old air out,
new air in!
• Relieves shortness of breath and causes
general relaxation
• Rescue breathing for acute dyspnea
Bianchi B et al. Chest 2004; (125): p. 459-465.

77. Treatment

78. Treatment Precautions and contraindications
Long-acting β2-agonist Should be used with caution in patients with pre-existing cardiovascular disease1
Should not been used without ICS in patients with features of asthma2
Long-acting muscarinic
antagonist
Used in patients at high risk for cardiovascular disease3
Caution advised in patients with narrow angle glaucoma, kidney problems or bladder-
neck obstruction4
Inhaled corticosteroids Use is associated with increased risk of pneumonia, tuberculosis,
osteroporosis, skin thinning/easy bruising, cataracts, diabetes and
oropharyngeal candidiasis5
Should be used with caution in patients who are being treated/have been
treated in the past for tuberculosis6
Safety issues associated with bronchodilators
and ICS in patients with comorbidities
1. Decramer ML, et al. Int J COPD 2013
2. GINA 2014; 3. Oba Y, et al. Int J COPD 20084. Spiriva® Summary of Product Characteristics 2013
5. Price D, et al. Prim Care Respir J 2013
6. Flixotide® Summary of Product Characteristics 2014

79. Treatment Precautions and contraindications
Phosphodiesterase
Type 4 inhibitor
Should be used with caution in underweight patients owing to unexplained
weight loss seen in controlled studies1
Use not recommended in patients with severe immunological disease,
severe acute infectious disease, congestive heart failure or cancer2
Should be used with caution in patients with depression1
Xanthines Has significant interactions with commonly used medications such as
digitalis and coumadin1
Precaution also advised in patients with congestive heart failure, liver
problems, or a history of seizures3
Safety issues associated with roflumilast and
theophylline in patients with comorbidities
1. GOLD 2017
2. DAXAS® Summary of Product Characteristics 2013
3. Slo-Phyllin® Summary of Product Characteristics 2014

81. THANK
YOU