COPD is associated with systemic inflammation that can lead to several extra-pulmonary effects and comorbidities. Low-grade systemic inflammation in COPD patients is characterized by elevated levels of pro-inflammatory cytokines and acute phase proteins. This systemic inflammation may originate from pulmonary inflammation spilling over into the systemic circulation, or from other sources like smoking, hypoxia, or bacterial products during exacerbations. Systemic inflammation in COPD has been implicated in several systemic effects and comorbidities including weight loss, muscle dysfunction, cardiovascular diseases, osteoporosis, and depression. Treatments like pulmonary rehabilitation, smoking cessation, and some medications can help reduce systemic inflammation and its associated manifestations in COPD.

1. COPD:
SYSTEMIC
INFLAMMATION OR
SYSTEMIC
MANIFESTATIONS
BY
WAHEED SHOUMAN
PROFESSOR OF CHEST MEDICINE
ZAGAZIG UNIVERSITY

2. Define: Manifestation
A symptom or sign of an ailment

3. Define: Sequelae
• A condition that is the consequence of a previous
disease or injury
•A pathological condition resulting from a disease,
injury, or other trauma
• Conditions which result from an event

4. Define: Effect
Cause (something) to happen; bring about

5. Define: Consequence
A phenomenon that follows and is caused by some
previous phenomenon

6. Define: Complication
A secondary disease or condition aggravating an
already existing one
Any disease or disorder that occurs during the course
of (or because of) another disease
Complication, in medicine, is an unfavorable evolution
of a disease, a health condition or a medical
treatment.

7. Define: Comorbidity
In medicine, comorbidity (literally "additional
morbidity") is either: * The presence of one or more
disorders (or diseases) in addition to a primary
disease or disorder; or * The effect of such additional
disorders or diseases
the presence of two or more illnesses in the same
person at the same time

8. Define: COPD

9. COPD
ATS/ERS/GOLD/ESCDT “a preventable and
treatable disease state characterized by
airflow limitation that is not fully
reversible(with significant extra-
pulmonary effects). The airflow limitation
is usually progressive and is associated
with an abnormal inflammatory response
of the lungs to noxious particles or gases,
primarily caused by cigarette smoking”

10. Systemic abnormalities of COPD
• Weight loss and nutritional abnormalities
• Skeletal-muscle dysfunction
• Cardiovascular diseases
• Diabetes/glucose intolerance
• Osteoporosis and fractures
• Depression
• Autoimmune disorders
• Other: cataracts, glaucoma, peptic ulcer,
impotence, gastroesophageal reflux

12. Is COPD the cause

14. Low grade systemic inflammation
 It is two-to-four folds elevation in circulating
levels of pro-inflammatory and anti-inflammatory
cytokines, naturally occurring cytokine antagonists,
acute phase proteins, as well as minor increase in
counts of neutrophils and natural killer cells
 Chronic systemic inflammatory syndrome:
systemic inflammation with major risk factor
(smoking, hyperlipidemia, obesity, hypertension)

15. ORIGIN OF SYSTEMIC INFLAMMATION IN
COPD:
1- “Spill over” from the pulmonary
inflammation
2- Inflammatory reaction to tissue hypoxia
3- The reaction induced by bacterial product
during exacerbations
4- Hyperinflation
5- Smoking effect
6- Autoimmune theory
7- Genetic theory
8- Inflamm-ageing

16. Why there is no correlation between lung and systemic
levels of inflammatory mediators:
1. A mediator or cytokine reach the circulation according
to the leakability of endothelium and protein size
2. Facilitated transport may play a role e.g. through
migration of activated macrophages
3. Protein concentration is difficult to quantify in airway
secretions
4. A protein may be produced in the interstitium and not
measured in airway secretions
5. A cytokine may be produced in the lungs and promote
secretion of another one in the same compartment or
another one
6. The lowest the pulmonary function, the highest the
vascular permeability

17. Smoking
Smoking induces a low-grade of systemic
inflammation and epithelial dysfunction, being a risk
factor for both COPD and cardiovascular diseases.
Smoking cessation does not lead to perpetuation
of pulmonary inflammation
Smoking per se induce increase permeability of
pulmonary vessels

18. Systemic inflammation has been implicated in
the pathogenesis of the majority of COPD systemic
effects, including weight loss ,skeletal muscle
dysfunction, cardiovascular diseases and
osteoporosis

20. Source of systemic inflammation

24. Inflamm-ageing
Chronic systemic inflammatory syndrome is
present with normal ageing that predispose to many
chronic illnesses including COPD
 This is attributed to lifelong antigenic exposure
leading to genetic modifications
More than 50% of people>65 years old have at
least three medical conditions, and one fifth have
five or more

26. Diagnostic components of chronic systemic
inflammatory syndrome
• Age older than 40 years
• Smoking for more than 10 pack-years
• Symptoms and abnormal lung function compatible
with COPD
• Chronic heart failure
• Metabolic syndrome
• Increased C-reactive protein
At least three components are needed for diagnosis

27. Low grade systemic inflammation
 ICS reduce systemic inflammation markers in
COPD
LVRS reduce exacerbations, HRQL, exercise
tolerance, and systemic inflammation but not local
inflammation
LABA and long acting para-sympatholytics have
the same effects
Quitting smoking has the same effects

29. Systemic inflammation in COPD
• No effect , even deleterious, effect of anti-
inflammatory systemic drugs as anti-TNF (infliximab)
•Decreased systemic and local inflammation with
specific PDE4-inhibitors cilomilast and roflumilast
but no long term follow up
•Pulmonary rehabilitation programs decrease the
systemic manifestations of COPD

30. AECOPD AND SYSTEMIC INFLAMMATION
Inflammatory mediators which were shown to
increase during AECOPD:
CRP, interleukin-8, TNF-α, leptin, endothelin-1,
eosinophilic cationic protein, myeloperoxydase,
fibrinogen, interleukin-6, α1-antitripsin, leukotrienes
E4 and B4.

31. GENETICS OF SYSTEMIC INFLAMMATION IN COPD

32. “‫كمثل‬ ‫تراحمهم‬ ‫و‬ ‫توادهم‬ ‫في‬ ‫المؤمنين‬ ‫مثل‬
‫الواحد‬ ‫الجسد‬.‫عضو‬ ‫منه‬ ‫اشتكي‬ ‫اذا‬‫تداعي‬‫ل‬‫ه‬
‫الجسد‬ ‫سائر‬‫بالسهر‬‫و‬‫الحمي‬”
Co-morbidities and consequences
Inflammation

33. COPD
“A CHRONIC INFLAMMATORY DISEASE WITH
PROGRESSIVE IRREVERSISIBLE AIRFLOW
LIMITATION.”

34. Weight loss
1. Systemic inflammation
2. Malnutrition
3. Hypoxemia
4. hypermetabolism
 BMI is a documented prognostic factor in COPD

35. Potential mechanisms of skeletal muscle dysfunction in
chronic obstructive pulmonary disease
1. Sedentary life
2. Nutritional abnormalities/cachexia
3. Tissue hypoxia
4. Systemic inflammation
5. Skeletal muscle apoptosis
6. Oxidative stress
7. Abnormal nitric oxide regulation
8. Tobacco
9. Individual susceptibility
10.Hormone alterations
11.Electrolyte alterations
12.Drugs

36. Potential mechanisms of skeletal muscle
dysfunction in chronic obstructive pulmonary
disease

38. Weight loss and muscle wasting
 No effect of recombinant IGF-1
 Controversy of GH administration
 Controversy of testosterone administration
 Good effect of nutritional support and
rehabilitation

39. Obesity paradox
Obesity increase the cardiovascular and all cause
mortality in stage one and two COPD]
 Obesity decrease the relative mortality risk in stage
three and four COPD
 These findings are also found in malignancies,
chronic heart diseases, renal failure and AIDS

40. Cardiovascular abnormalities
In mild to moderate COPD, cardiovascular disorders
are attributed to 50% of hospitalization and one third
of all causes of death in these patients
Patients with the lowest FEV1 (unrelated to
smoking or COPD) had two times higher risk for death
from cardiovascular cause
COPD increase the risk for IHD (irrespective of
smoking) by 24-26%, while hyperlipidemia increase
the risk by 21-25%

41. Cardiovascular abnormalities
Cardiovascular events are highest among smokers
with higher rate of decline in FEV1
Among life time non-smokers, accelerated decline
of FEV! Is associated with 5-10 fold increase in cardiac
death
Chronic bronchitis symptoms (cough) is associated
with 50% risk for coronary death
For each 10% decrease in FEV1, CV death increase
by 28%
Reduced lung function increase the risk of ischemic
stroke , but weaker than that for IHD

42. Causes of osteoporosis in COPD
• Smoking
• Increased alcohol intake
• Vitamin D levels
• Genetic factors
• Treatment with corticosteroids
• Reduced skeletal muscle mass and strength
• Low BMI and changes in body composition
• Hypogonadism
• Reduced levels of insulin-like growth factors
• Chronic systemic inflammation

43. Neurological abnormalities
Subclinical autonomic dysfunction
Peripheral neuropathy
Ischemic stroke

44. Ptyriasis versicolor

45. Bronchial asthma

46. IPF

47. MECHANICAL VENTILATION

48. BRONCHIECTASIS

49. VITILIGO

50. SYSTEMIC INFLAMMATION IN ASTHMA
Data regarding systemic inflammation in patients with
asthma are rare. The association of systemic
inflammation with comorbidities in asthma has not
been investigated so far

51. Thank
you