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© SUPPLEMENT TO JAPI • FEBRUARY 2012 • VOL. 60
Systemic Manifestations of COPD
BV Murali Mohan*, Tiyas Sen*, R Ranganatha*
O
Introduction
ver 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.
Currently, the “GOLD” definition of COPD includes the
words “some significant extrapulmonary effects that may contribute
to the severity in individual patients”.1It has even been suggested
that COPD should be renamed a “chronic systemic inflammatory
syndrome” (Fabbri and Rabe)
Extra-pulmonary effects include systemic inflammation,
nutritional abnormalities and weight loss, skeletal muscle
dysfunction and additional organ effects.3-6
Systemic Manifestations and
Co-morbidities
Systemic consequences are non-pulmonary manifestations
of COPD with an immediate cause-and-effect relationship.
Co-morbidities are diseases coexisting with COPD, without
necessarily a cause-effect relationship.
This review attempts to answer the following questions:
1.
Is there a significant amount of systemic inflammation in
COPD?
2.
What are the causes of this systemic inflammation?
3.
What are its consequences?
4.
How is this relevant to our clinical practice?
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. The markers of systemic inflammation that
are consistently increased are hs C-Reactive Protein (hsCRP),
fibrinogen, ferritin, the total leucocyte count, Reactive Oxygen
Species, interleukins and other cytokines and Transforming
Growth Factor Beta1 (TGF b 1) and Tumor Necrosis Factor-a
(TNF-a) receptor polymorphisms.Our own data shows
significantly elevated mean levels of ESR, CRP, TLC, neutrophils,
ferritin and fibrinogen in COPD subjects compared with controls.
Hemoglobin showed a much wider variation, with both anemia
and polycythemia being found to a greater extent in the COPD
than in the control group. (PrashanthaB , Murali Mohan.
Unpublished data)
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.
Discordance between TNF-α and IL-8 values in induced
*
Narayana Hrudayalaya Multispeciality Hospital, Bangalore
sputum and plasma suggests that systemic inflammation in
COPD is independent of pulmonary inflammation.7,8
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.9,10
Another trigger may be the 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.
Several HIF-1 target genes maybe involved in these processes.11
TNF-α levels were significantly correlated with the severity of
arterial hypoxaemia.12,13 Improved survival in patients receiving
domiciliary oxygen therapy (LTOT), might be due to decreased
systemic inflammation.2
Adipokines may represent the link between COPD and
its co-morbidities. Circulating leptin may promote systemic
inflammation in stable COPD. Associations, though inconsistent,
exist between plasma concentrations of leptin and soluble TNF
receptor-55, after adjustment for fat mass. Increased leptin
concentrations and leptin receptor polymorphisms may cause
a decline in lung function, independent of obesity, in smokers
with COPD. In mice, systemic adiponectin had an independent
protective effect on the lung through inhibition of alveolar
macrophage-related inflammation in mice. It is not known if
the same is true in humans.14,15
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.17,18
Consequences of Systemic
Inflammation
Several systemic manifestations and “chronic complex
co-morbidities of COPD have been described, repeatedly and
reliably.19-21
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
© SUPPLEMENT TO JAPI • FEBRUARY 2012 • VOL. 60 45
Table 1 : Prevalence of co-morbidities in COPD
Causes
● Noxious
fume
exposure
Tobacco
smoke or
environmental
pollutants
(indoor
and
outdoor)
Amplifying
processes
● Genes
● Epigenetic
processes
● Immune system
● Odixative stress
Tissue events
● T-cell activation
● Inflammatory
cascade
● Mediator release
● Apoptosis
● Telomere shortening
● Auto-immunity
● Systemic
inflammation
Pathological
processes
Chronic bronchitis
Emphysema
Bacterial
colonisation
Atherosclerosis
Metabolic
syndrome
Systemic
consequences
COPD
CAD
CeVD
PVD
Diabetes
DNA damage
Cancer
Cachexia
Muscle wasting
Depression
Fig. 1 : Pathobiology of COPD
Obstructive sleep apnoea
Depression
The reported prevalence of co-morbidities in COPD varies
considerably, but are impressively high across all studies. We
pooled the data from several studies (van Manen et al, Mapel
et al, Soriano et al, Sidney et al and Walter and Thomashow) to
obtain the following prevalences (Table 1):
The systemic inflammation may initiate or worsen preexisting co-morbidities. Some patterns of disease including
COPD, diabetes mellitus/ metabolic syndrome, Obstructive Sleep
Apnoea, coronary artery disease, cerebro-vascular disease and
congestive heart failure (CHF) occur together more frequently
than can be expected by mere chance.
COPD and the Heart
COPD and CAD are closely linked, with often a failure
to recognize one in the presence of the other. Several studies
indicate a three-fold cardiovascular risk in COPD compared to
the general population. Cardiovascular mortality accounts for
14%- 42 % of the overall observed mortality in COPD, compared
with 14% -61 % due to COPD. Cardiovascular co-morbidity
existed in 13%- 65 % of COPD subjects in other studies.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. CAD and cerebrovascular disease
(together CVD) add significantly to overall health burden of
patients with COPD. The wide ranges in the studies quoted
above raise some disquiet about the data.22-25
Poor lung function is a risk factor for CVD, atrial fibrillation,
ventricular dysrhythmias, and left ventricular diastolic
dysfunction. When stratified according to quintiles of FEV1,
there is a linear increase in mortality (CVS and all-cause)
among COPD subjects, comparable with hypercholesterolemia.
Similarly, vital capacity index correlates inversely with CVS
mortality and all-cause mortality, across age and gender, in fact
becoming even stronger with increasing age and in women.26-31
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).26 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,.
Airflow limitation is further worsened by mucosal congestion,
%
%
Comorbid condition
prevalence
prevalence
Arthritis
47
Psychiatric problems
22
Cardiovascular disease
20.1
Gastro-intestinal
39.8
Hypertension
20.2
Cancer
4.7
Diabetes
2.9
Osteoporosis
32
Dyslipidemia
11.6
Comorbid condition
smoking, muscle weakness and reduced lung compliance in
heart failure.27 In patients with heart failure, salt loading induces
bronchial hyperresponsiveness, while removing excess salt and
water by ultrafiltration has the opposite effect.29-31
While smoking is a common risk factor for both COPD and
CAD, the role of other triggers of systemic inflammation is
being increasingly recognized. This will be an important area
of study in the non-smoking COPD population, including those
with“tuberculosis-related COPD”.
COPD and Osteoporosis
Patients with COPD show increased prevalence of
osteoporosis. This is at least partly independent of the effects
of steroids, being seen even in the absence of steroid use.
Vertebral fractures may be present in 50% of steroid-naive
males with COPD.32 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.33 High levels of TNF-a are found in
osteoporosis associated with both post-menopausal states and
COPD.34,35 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.
COPD and Diabetes
Systemic inflammation also explains the association between
COPD and diabetes. The prevalence of diabetes, quoted at only
2.9% (Table 1) is probably an underestimate, being heavily
influenced by the study of Sidney et al which had the largest
numbers (45066 subjects) and the lowest prevalence (2%). 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). Methodological variation may account for
the differences as Sidney et al drew their figures from the KaiserPermanente Medical Care program’s listing of COPD patients’
cardiovascular hospitalisations, while Walsh and Thomashow
derived their data from a COPD National foundation database.3638
Overall, the consensus, is that there is a truly increased
prevalence of Type 2 Diabetes mellitus in COPD.
Systemic inflammation may also explain why patients with
COPD have an increased risk of developing type 2 diabetes.
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- which
further strengthens the association.39-41 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
46
© SUPPLEMENT TO JAPI • FEBRUARY 2012 • VOL. 60
the development of co-morbidities.42,43
survival and quality of life in patients with COPD.
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.44 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.45,46
The search for co-morbidities in a patient with COPD,
and conversely, for COPD in a patient with recognized comorbidities, 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) while unproven in this situation, should
not be denied to patients. Pharmacologic interventions are still
unclear, but beta-blockers, anti-oxidants and inhaled corticosteroids 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.53 It is tempting to speculate that statins may
be recommended at the level of primary prevention in patients
with COPD.
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.
Our own still unpublished data agrees with this finding even
among Indian patients, with COPD patients showing significant
mean decreases in lean body mass (over 4%) and serum albumin
(4.9 g/L), compared with placebo (Prashantha B, Murali Mohan
unpublished data).
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.
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. 46-49
COPD and Depression
COPD and depression are significantly associated due to
multiple reasons. About 40% of patients with COPD are found
to have depression, compared to a prevalence of about 15-20 %
in the general population.50 We found a prevalence of close to
90% of at least mild depression (as measured on the Hamilton
depression scale) in patients admitted with COPD.51
Conclusions
COPD is a disease characterized by systemic inflammation,
systemic consequences, and many chronic and complex comorbidities. 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.
Where 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.
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