This document discusses systemic inflammation and comorbidities in COPD. It notes that COPD is associated with various important comorbidities beyond the lungs, and inflammation is seen systemically, not just in the lungs. Common comorbidities discussed include cardiovascular diseases like heart disease, hypertension, and stroke. It also mentions increased risk of osteoporosis, diabetes, lung cancer, and other conditions. The systemic inflammation in COPD can be caused by factors like smoking and hypoxia and may contribute to the development and severity of these comorbid conditions.

1. DR ASHIQUE ALI

2.  Gold update 2015
“ COPD a common preventable and treatable
disease, is characterized by persistent airflow
limitation that is usually progressive and associated
with an enhanced chronic inflammatory response in
the airways and the lung to noxious particles or
gases.
Exacerbations and comorbidities contribute to the
overall severity in individual patients.

3. Introduction
 Over the last two decades, it has gradually been
recognised that:
 1. Chronic Obstructive Pulmonary Disease (COPD) is
associated with various important co-morbidities
 2. Inflammation in COPD is not confined to the lung
alone but is also seen systemically.

4.  Currently, the “GOLD” definition of COPD includes
the words “some significant extrapulmonary effects
that may contribute to the severity in individual
patients”.
 It has even been suggested that COPD should be
renamed a “chronic systemic inflammatory
syndrome” (Fabbri and Rabe).

5. Systemic Inflammation in COPD
 The presence of systemic inflammation in COPD is
undeniable.
 Several studies have shown that markers of systemic
inflammation are increased in subjects with stable
COPD, they appear early in COPD and increase with
increasing COPD severity

6. The markers of systemic inflammation that are
consistently increased are
 hs C-Reactive Protein (hsCRP),
 fibrinogen,
 ferritin,
 total leucocyte count,
 Reactive Oxygen Species,
 Interleukins and other cytokines
 Transforming Growth Factor Beta1 (TGF b 1)
 Tumor Necrosis Factor-a (TNF-a) receptor
polymorphisms.

7.  Two explanations for the systemic inflammation of
COPD have been described:
 1. Spillover of inflammation from the pulmonary into
the systemic compartment.
 2. A pro-inflammatory phenotype, where systemic
inflammation occurs independent of the pulmonary
inflammation.

8.  Discordance between TNF-α and IL-8 values in
induced sputum and plasma suggests that systemic
inflammation in COPD is independent of pulmonary
inflammation

10. Causes of the Systemic
Inflammation
 Smoking, a factor common to COPD and several of its
comorbidities may trigger systemic inflammation by
inducing oxidative stress, as well as by producing
peripheral vascular endothelial dysfunction.
 These processes occur even in smokers of only a few
pack-years and in passive smokers

11. Inflammatory markers in COPD
 In COPD ↑ levels of inflammatory cytokines, acute
phase proteins, and markers of oxidant stress (Oudijk
EJ, et al. Eur Respir J Suppl 2003;46:5s–13s)
 Cytokines in COPD include TNF-α, TGF-β, interferon-
γ, and ILs- 6 and 8 (Wouters EF et al.Proc AmThorac
Soc 2005;:26–33)
 COPD with lowest FEV1 have the highest levels of CRP,
fibrinogen, and other systemic inflammatory markers,
while those with the highest FEV1 have the lowest
values (Circulation 2003; 107:1514–1519)

12.  ↑cytokines and CRP are associated with heart disease,
and atherosclerosis in patients with COPD (van Eeden
SF, et al. Proc Am Thorac Soc 2005;:61–7)
 CRP and fibrinogen, are elevated in smokers, and ↑
fibrinogen levels in smokers are associated with ↓ lung
function and ↑ risk for COPD (Dahl M,et al. AJRCCM
2001;164(6):1008–11)
 ↑ CRP is an independent risk factor for CAD,
myocardial infarction and stroke (PRIME Study. 2003;
23: 1255–61)

13.  Another trigger is hypoxia of severe COPD.
 Hypoxia-inducible factor (HIF)-1 may signal the
presence of hypoxia to the gene-transcriptional
machinery in various tissues, and the need for adaptive
responses to this hypoxia.
 HIF-1 activates a number of target genes involved in
angiogenesis, energy metabolism, erythropoiesis,
inflammation, cell proliferation, vascular remodeling,
and vasomotor responses.

14.  Several HIF-1 target genes maybe involved in these
processes.
 TNF-α levels were significantly correlated with the
severity of arterial hypoxaemia.
 Improved survival in patients receiving domiciliary
oxygen therapy (LTOT), might be due to decreased
systemic inflammation

15.  Adipokines may represent the link between COPD
and its co-morbidities.
 Circulating leptin may promote systemic
inflammation in stable COPD.
 Anti-elastin antibodies have been demonstrated in
COPD.
 Auto-immunity may play a role, and explain why
COPD processes persist even after quitting smoking.

16.  Accelerated lung ageing may underlie the systemic
inflammationof COPD.
 Telomeres, “ protective caps” on the ends of
chromosomes, get progressively shorter as cells divide
and this is accelerated with oxidative stress.
 COPD, which is characterized by oxidative stress, may
therefore be a disease of accelerated ageing of both the
lung and other systems.

18. COPD is a complex disease
 On the one hand, the latter could be the consequence
of the former, the socalled “systemic effects” of
COPD . On the other hand, they may represent the
cooccurrence of highly prevalent diseases
(cardiovascular, metabolic, muscular, and bone
disorders) in aged patients (comorbidities)

19. Consequences of Systemic
Inflammation
 Several systemic manifestations and chronic complex
co-morbidities of COPD have been described
 Skeletal muscle wasting
 Cachexia: loss of fat-free mass
 Lung cancer (small cell, non-small cell)
 Pulmonary hypertension
 Ischaemic heart disease: endothelial dysfunction
 Congestive cardiac failure
 Osteoporosis
 Normocytic anaemia
 Diabetes mellitus/ Metabolic syndrome
 Obstructive sleep apnoea
 Depression

20. ACCORDING TO Georgios Hillas, Fotis Perlikos,Ioanna
Tsiligianni2, Nikolaos Tzanakis
International Journal of COPD ON 2015 JAN
Respiratory comorbidities
Asthma
Lung cancer
Pulmonary fibrosis
Cardiovascular comorbidities
Hypertension
Congestive heart failure
Coronary heart disease
Atrial fibrillation
Pulmonary artery hypertension and subsequent right
heart failure

21. Venous thromboembolism
Stroke
Metabolic comorbidities
Diabetes and metabolic syndrome
Osteoporosis
Cachexia and myopathy
Mental comorbidities
Other comorbidities
Obstructive sleep apnea syndrome
Gastroesophageal reflux disease
Chronic renal failure

23. Gold 2015
COPD patients are at increased risk for:
• Cardiovascular diseases
• Osteoporosis
• Respiratory infections
• Anxiety and Depression
• Diabetes
• Lung cancer
• Bronchiectasis
These comorbid conditions may influence mortality and
hospitalizations and should be looked for routinely, and
treated appropriately.

24. Prevalence of the most common
COPD comorbidities (%)

28. COPD and the Heart
 COPD and CAD are closely linked, with often a failure
to recognize one in the presence of the other.
 Cardiovascular mortality -14%- 42 % of the overall
observed mortality in COPD, compared with 14% -61
% due to COPD.

31.  Data from the TORCH study also showed that
cardiovascular causes accounted for about 27% of the
overall mortality.
 Data from the large Saskatchewan data base suggest
that patients with COPD had more deaths and
hospitalisations for cardiovascular causes than from
COPD itself.

32. Poor lung function is a risk factor for
 Atrial fibrillation,
 ventricular dysrhythmias, and left ventricular diastolic
dysfunction.
 When stratified according to FEV1, there is a linear
increase in mortality (CVS and all-cause)among COPD
subjects, comparable with hypercholesterolemia
 Every 10% decline in FEV1, cardiovascular mortality
increases by 28% showing a clear relation between
overall cardiovascular death and low lung function

33.  Participants in the National Health and Nutrition
Examination Survey (NHANES) Epidemiologic
Follow-up Study with the lowest levels of FEV1 showed
5 times higher risk of death by ischemic heart
disease.
 vital capacity index correlates inversely with CVS
mortality and all-cause mortality, across age and
gender, becoming even stronger with increasing age
and in women

34.  Recent evidence suggests that beta-blocker co-
prescription improves cardio-vascular outcomes and
survival in patients with COPD.
 Long-term cardioselective beta-blockade in patients
with COPD was shown to be safe and well-tolerated in
a Cochrane data base meta-analysis of 20 randomized,
controlled, crossover trials of cardioselective beta1
blockers in patients with COPD (without CHF).

35.  Unrecognized heart failure in COPD causes confusion,
worsens outcomes and complicates management.
 Almost 50% of patients in one study of heart failure with
preserved systolic function met the criteria for airflow
obstruction (FEV1/FVC% < 0.7).
 In heart failure, the electrolyte derangements seem to
increase bronchial hyperresponsiveness,.

36. Endothelial dysfunction and COPD
 The systemic inflammation in COPD ,key determinant
for the development of pulmonary and systemic
endothelial dysfunction.
 Other factors could be involved in maintaining
endothelial integrity, such as circulating endothelial
progenitor cells (CEPCs).
 The number of CEPCs appears to be reduced in the
systemic circulation and increased in the pulmonary
circulation of patients with COPD

37. Coagulopathy and COPD
 The systemic inflammation present in COPD appears to
induce a ‘‘pro-coagulant’’ state.
 In the basal state, COPD patients exhibit abnormally high
levels of tissue factor (tissue factor pro-coagulant activity)
and Factor VIIa , and their fibrin clots are resistant to lysis .
 It was recently discovered that coagulation is altered in
patients with COPD.
 An electron microscopy study showed that fibrin clots
isolated from the plasma of COPD patients are denser
and more resistant to lysis than those from control
subjects with an equivalent circulating fibrinogen
concentration(Kaczmarek P, Sladek K, Stepien E, et al.)

38. Systemic venous thromboembolism and COPD
 The three factors of Virchow’s triad are observed in
COPD (systemic venous endothelial dysfunction,
coagulopathy and venous stasis due to a physical
inactivity), which explains their predisposition to
venous thromboembolism (VTE).
 During COPD exacerbations, VTE is found in 3–29%
of cases

39.  There are no specific clinical, biological or radiological
signs indicative of VTE.
 It should be suspected during COPD exacerbation -chest
pain or syncope, or a fall in arterial carbon dioxide tension
in a patient who is usually hypercapnic.
 VTE during a COPD exacerbation prolongs hospitalisation
by 4.4 days and increases the 1-year mortality rate by 30%
(Sidney S, Sorel M,).
 Failure to diagnose VTE and to institute suitable
anticoagulant therapy increases the death rate by 25%
during hospitalisation.

40. Anemia
 Anemia has been described with variable frequency in
the COPD population, from 3.3% in NHANES to 6.2%
among COPD outpatients, and up to 17% among
COPD inpatients.
 It has been hypothesized that anemia in COPD shares
mechanisms with other anemias of chronic disease
with persistently elevated interleukins (especially IL-1)
interfering with the response to erythropoietin.
 A recent cross-sectional study found higher levels of
erythropoietin in COPD patients with anemia,
compared with those with normal hemoglobin.

41.  Different COPD outcomes, including poor functional
status,frequent exacerbations and increased health
care-related direct and indirect costs have been
associated with the presence of anemia.
 Cohort studies suggest that survival also seems to be
affected by the hemoglobin level, being lower in those
with anemia than in those with a normal level or
polycythemia.
 No specific treatment recommendations for coexistent
anemia in COPD are currently available

43. COPD and Osteoporosis
 Both osteopenia and osteoporosis are increased among
patients with COPD, with the severity of COPD related
to the prevalence of osteoporosis
 This is at least partly independent of the effects of
steroids, being seen even in the absence of steroid use.

44.  Osteoporosis may be related to elevated TNF-a and
Interleukin-1, which stimulate the differentiation of
macrophages into osteoclasts via mesenchymal cells
releasing receptor activator of nuclear factor-k B
ligand, a member of the TNF-a superfamily.

45.  This suggests that COPD associated osteoporosis is
also due to systemic inflammation, and therefore a
systemic Consequence
 Age, limited physical activity, low Body Mass Index
(BMI), smoking, decreased gonadal function (due to
both age and smoking) and malnutrition are also
contributing factors.

46. COPD and Body Weight
 Skeletal muscle wasting is a typical co-morbidity of
COPD.
 Skeletal muscle itself can contribute to systemic
inflammation.
 Wasting is commonly seen in patients with COPD,
increasing in prevalence from 20% in early, stable
COPD to 35% in patients in severe COPD patients
enrolled for pulmonary rehabilitation.
 The loss of body mass appears to mainly occur in fat-
free mass (FFM), typically skeletal muscle, while fat
mass is relatively preserved

47.  The mechanism of weight loss appears to be related to
1. Increased levels of IL-6 in particular, and systemic
inflammation in general.
2. Decreased intake, though this is mainly during acute
exacerbations.
3. Hypoxia
4. Endocrine changes, including Growth Hormone
resistance, reduced Insulin-like Growth Factor- 1
(IGF-1) gene expression and low-levels of IGF-1
binding proteins, and reduced testosterone levels

48.  The loss of muscle will have an adverse impact on
respiratory and peripheral muscle function, exercise
capacity, and health status.
 Weight loss has been shown to be an important
negative predictor for survival in COPD.
 BMI is one of the four parameters used in calculating
the BODE index, a validated prognostic score of
mortality in COPD

49. COPD and Diabetes
 Systemic inflammation also explains the association
between COPD and diabetes.
 prevalence of diabetes, quoted at only 2.9% is
probably an underestimated value
 It is heavily influenced by the study of Sidney et al
which had the largest numbers (45066 subjects) and
the lowest prevalence (2%)

50.  A much higher prevalence of diabetes in COPD was
reported by Mapel et al (12% of 200 subjects), and
Walsh and Thomashow (16% of 3000 subjects)
 Overall, the consensus, is that there is a truly increased
prevalence of Type 2 Diabetes mellitus in COPD.

51.  The presence of inflammation and of markers of inflammation
(fibrinogen, circulating white blood cell count and lower serum
albumin) predicts the development of diabetes and metabolic
syndrome.
 Patients with Type 2 diabetes mellitus have increased circulating
levels of TNF-a, interleukin(IL)-6 and CRP -also risk factors for
cardiovascular events.
 Diabetes is independently associated with reduced lung
function, and, with obesity could further worsen COPD severity.
 It appears that there is a fairly complex interaction between
smoking, diabetes/ metabolic syndrome, COPD, cardiovascular
disease and obesity leads to the development of co-morbidities.

52.  Some COPD patients may show features only of the
metabolic syndrome.
 Metabolic syndrome is characterized by abdominal
obesity, elevated triglycerides, atherogenic
dyslipidaemia, elevated blood pressure, high blood
glucose, and underlying insulin resistance.
 It is also associated with a pro-thrombotic and a pro-
inflammatory state with increases in plasminogen
activator inhibitor, CRP and fibrinogen.
 Some part of the association is independent of steroid
treatment and decreased physical activity

53. COPD and lung cancer
 COPD is not only a risk factor for lung cancer, but also
for death from lung cancer
 The presence of moderate or severe airflow
obstruction is a significant predictor of incident lung
cancer
(Mannino DM et al. Arch Intern Med 2003;113:1475-1480 )
 Hypoxia-inducible transcription factors (HIF) may
promote angiogenesis and involved in both ischemic
diseases and cancer
(Constans A et al The Scientist 2004;18:20-21)

54.  Patients with COPD at the time of lung cancer diagnosis
have a poorer prognosis .
 3-year survival in the COPD-lung cancer group was 15%
versus 26% in the lung cancer without COPD group
 Very recently, genome analyses of patients with COPD and
lung cancer have shown susceptibility loci common to both
diseases on several chromosomes (e.g. 15q25, 4q31 and
6p21) .
 Role for epigenetic changes common to the development of
lung cancer and COPD has also been suggested.

56. Gastroesophageal Reflux Disease
 Consistently higher prevalence of the disease
among those with COPD than in the general population.
 Identification of GERD frequently among COPD
individuals with predominantly bronchitis phenotypes
(33.6% compared to 27.6% in those without chronic
bronchitis).
 The role of mechanical factors such as persistent cough,
changes in thoracic and abdominal pressures and the
development of hiatal hernias (present in 13% of COPD
individuals) as explanations for the COPD-GERD
association.

58. COPD and Depression
 About 40% of patients with COPD are found to have
depression, compared to a prevalence of about 15-20 %
in the general population
 Loss of independence with increasing disability in
COPD can cause, or aggravate, depression. A
predisposition to depression may increase the risk of
smoking, as nicotine has a mood-elevating effect

59. Obstructive Sleep Apnea
 Population-based studies have identified sleep apnea
among COPD patients with a frequency similar or just
slightly higher than the general population: between
8% and 14%
 Overlap syndrome is the increase in mortality for those
with untreated sleep apnea
 Clinical findings that should prompt an evaluation of
sleep apnea include pulmonary hypertension or right
heart failure unexplained by or out of proportion to
the degree of obstruction.

60. Chronic renal failure
 Renal complications of COPD are common, especially
in patients with hypoxemia and hypercapnea.
 The arterial rigidity and endothelial dysfunction
caused by COPD lead to a decreased normal renal
functional reserve.
 Impairment of renal functional reserve in COPD
patients is correlated with more severe airway
obstruction and inflammation
 COPD have approximately twice the incidence of acute
renal failure, and three times the prevalence of
diagnosed chronic renal failure.

61.  Chronic renal failure often goes undiagnosed, and is a
particular concern in elderly COPD patients and in
COPD patients with cachexia
 Among COPD patients over 64 years of age, 25% may
have chronic renal failure even with normal serum
creatinine values.(Paz-Diaz H, Montes de Oca M,
Lopez JM, Celli BR et al)

62. Comorbidity Clusters in COPD
Phenotypes
 The improving definition of COPD phenotypes
continues to enhance our understanding of COPD-
related comorbidities.

63. Clusters of COPD Comorbidities Based on
Common Pathogenic Mechanisms
 1.Inflammation/ Immune Response
Asthma,pneumonia, IHD, osteoporosis, musculoskeletal
dysfunction, metabolic syndrome
 2. Apoptosis/Necrosis/Degeneration –
Cardiovasculardiseases, malignancies, metabolic syndrome,
osteoporosis, musculoskeletal dysfunction
 3. Trauma and Repair/Cell Proliferation
andNeoplasia/Fibrosis –
Malignancies,musculoskeletal dysfunction
 4. Thrombosis/Hemorrhage –
Pulmonary embolism,ischemic heart disease, cerebrovascular
diseases
 5. Unknown – Depression, chronic renal failure

64. Summary of Evidence Regarding the Frequency, Impact,
Phenotypic Associations and Areas of
Uncertainty Around the Reviewed COPD Comorbidities

65. How is this Relevant to Our Clinical Practice?
 Increasing recognition of systemic inflammation and
co-morbidities in COPD, and the understanding of its
molecular mechanisms, will hopefully offer new
strategies to improve survival and quality of life in
patients with COPD.

66. Treatment and management
 The cornerstone of management for COPD and
comorbidities is guideline-based treatment.
 The management and treatment of COPD is usually based
on GOLD guidelines
 There is little specific guideline guidance for administering
cardiovascular regimens to patients with comorbid COPD.
 As a result, β-blockers are frequently underused in
patients with COPD.
 Awareness is needed for patients with congestive heart
failure and COPD not to be denied β-blocker treatment.
 Cardioselective β-blockers improve the prognosis without
impairing lung function.

67.  Caution is needed because cardioselectivity decreases
as the dosage escalates.
 Patients with coronary heart disease should also not be
denied the protective effects of β-blockers.
 GOLD guidelines recommend the use of the general
coronary disease guidelines, and especially note the
use of selective β1 -blockers even in patients with
severe COPD.
 The use of angiotensin-converting enzyme (ACE)
inhibitors by smokers may protect against a rapid
decline in lung function and progression to COPD

68.  Treatment of OSAS does not differ between patients
with COPD and those without.
 Treatment of COPD patients with OSAS is based on
the treatment of constituent diseases (for COPD
bronchodilators, inhaled steroids when indicated,
rehabilitation, nutrition, domiciliary oxygen when
indicated, and for OSA weight loss and application of
continuous positive airway pressure [CPAP]).
 The goal of treatment is to maintain adequate
oxygenation at all times and to prevent sleep-
disordered breathing.

69.  chronic kidney failure in COPD patients, especially the
elderly, indicates that awareness is needed for
monitoring and addressing adverse effects caused
mainly by hydrosoluble drugs, which are cleared by the
kidney.
 Special attention is warranted for drugs like thiazides
or digoxin, used in the treatment of cardiovascular
comorbidities, but also antibiotics commonly used in
acute exacerbations of COPD

70.  Nonpharmacological treatment of COPD patients
includes smoking cessation (counseling plus
pharmacotherapy), influenza and pneumococcal
vaccination, and pulmonary rehabilitation.
 Pulmonary rehabilitation, has the potential to affect a
number of comorbidities
 Physical activity and regular exercise are proven to be
beneficial for multiple comorbidities, including
cardiovascular disease, diabetes, or musculoskeletal
diseases

71.  Management of COPD needs a systemic holistic
approach.
 Holistic approach includes COPD management based
on pharmacological and nonpharmacological
treatment, guideline-based management for specific
comorbidities, and modification of the risk factors for
COPD and comorbidities
 Some researchers have started to advocate for an
integrated care approach to the management of
patients with COPD.
 There is a need for a chronic care model approach to
the management of COPD, including automatic
screening for common comorbidities.

73. •COPD often coexists with other diseases
(comorbidities) that may have a significant impact on
prognosis.
•In general, presence of comorbidities should not
alter COPD treatment and comorbidities should be
treated as if the patient did not have COPD.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Comorbidities
© 2015 Global Initiative for Chronic Obstructive Lung Disease

74. •Cardiovascular disease (including ischemic heart
disease, heart failure, atrial fibrillation, and
hypertension) is a major comorbidity in COPD and
probably both the most frequent and most important
disease coexisting with COPD.
•Benefits of cardioselective beta-blocker treatment in
heart failure outweigh potential risk even in patients
with severe COPD.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Comorbidities
© 2015 Global Initiative for Chronic Obstructive Lung Disease

75. Osteoporosis and anxiety/depression: often under-
diagnosed and associated with poor health status and
prognosis.
Lung cancer: frequent in patients with COPD; the most
frequent cause of death in patients with mild COPD.
Serious infections: respiratory infections are especially
frequent.
Metabolic syndrome and manifest diabetes: more
frequent in COPD and the latter is likely to impact on
prognosis.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Comorbidities
© 2015 Global Initiative for Chronic Obstructive Lung Disease

76.  Search for co-morbidities in a patient with COPD, and
conversely, for COPD in a patient with recognized co-
morbidities, must head the list of changes in
management of patients with COPD
 Early recognition and early intervention should
improve outcomes.
 Preventive interventions, primary or secondary, may
be useful, and deserve further study.
 The benefits of smoking prevention/ cessation,
interventions to reach a healthy weight range, diet and
exercise and rehabilitation (pulmonary and cardiac)

77.  Pharmacologic interventions are still unclear, but
beta-blockers, anti-oxidants and inhaled cortico-
steroids are promising.
 Statins evoke the greatest interest, with at least one
randomized controlled trial and several observational
studies suggesting benefits from their use.
 Benefits described have included reductions in
mortality (COPD and all-cause), myocardial
infarctions, COPD exacerbations and hospitalisations
and intubations during exacerbations, as well as
slowing lung function decline.

78. Statin use and exacerbations in individuals with
chronic obstructive pulmonary disease.
Ingebrigtsen TS, Marott JL, Nordestgaard BG, Lange P, Hallas J, Vestbo J.
2015 THORAX JAN
 Statin use was associated with reduced odds of
exacerbations in individuals with COPD from the
general population,
 This was not apparent in those with the most severe
COPD without cardiovascular comorbidity.
 Statins may thus only associate with reduced risk of
exacerbations in patients with COPD with coexisting
cardiovascular disease.

79. Conclusions
 COPD is a disease characterized by systemic inflammation,
systemic consequences, and many chronic and complex co-
morbidities.
 All patients with COPD should be examined and investigated for
co-morbidities, and conversely, patients with any of the known
co-morbidities should be screened for COPD.
 If present these should be treated. Where not present, lifestyle
interventions such as smoking prevention and cessation, and
interventions such as diet control and exercise should be
advised.
 The role of pharmacological interventions, including statins,
deserves further studies.
 Greater efforts should be made at educating physicians and
patients about the existence of co-morbidities in COPD and the
need for screening and early intervention.

80. THANK YOU