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C L I N I C A L P E R S P E CT I V E S
Key words
COPD, chronic obstructive pulmonary disease,
chronic, lung disease, update.
Correspondence
Christine F. McDonald, Respiratory and Sleep
Medicine, Austin Hospital, Studley Road,
Heidelberg, Vic. 3084, Australia.
Email: christine.mcdonald@austin.org.au
Received 13 November 2012; accepted 28 May
2013.
doi:10.1111/imj.12219
Abstract
Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow
limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD
is associated with significant extrapulmonary manifestations, including ischaemic heart
disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common.
Spirometry remains the gold standard diagnostic tool. Pharmacologic and nonpharmacologic therapy can improve symptoms, quality of life and exercise capacity and,
through their effects on reducing exacerbations, have the potential to modify disease
progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines
recommending a stepwise escalating approach. Smoking cessation is paramount in
managing COPD, with promotion of physical activity and pulmonary rehabilitation
being other key factors in management. Comorbidities should be actively sought and
managed in their own right. Given the chronicity and progressive nature of COPD,
ongoing monitoring and support with timely discussion of advanced-care planning and
end-of-life issues are recommended.
Funding: None.
Conflict of interest: Christine McDonald has served on advisory
boards for GlaxoSmithKline, Novartis, Pfizer; received conference support from Nycomed; has given presentations at educational meetings sponsored by Boehringer Ingelheim and
Novartis.
854
Diagnosis
Spirometry is required to make a diagnosis of COPD. A
medical history and clinical examination may suggest the
diagnosis, but they are not reliable predictors of airflow
obstruction. In the presence of symptoms such as
2013 The Authors
Internal Medicine Journal 2013 Royal Australasian College of Physicians
Advances in COPD
Pathology
COPD is a chronic inflammatory airway disease, but
differs significantly from asthma in that the inflammation
is relatively resistant to treatment with corticosteroids.
Exposure to noxious injury triggers a predominantly
neutrophilic infiltration with activation of the innate
immune response. An inflammatory cascade ensues,
with induction of type 1 and type 17 T helper cells and
the subsequent development of transforming growth
factor -induced small-airway fibrosis and matrix
metalloproteinase elastic tissue destruction.9 These
responses appear to perpetuate even after removal of the
initial stimulus10 and may be associated with spillover of
the inflammatory response from the lungs to the systemic
circulation, leading to potential downstream effects, such
as arterial stiffness and its consequences. Parenchymal
destruction is associated with loss of lung tissue elasticity
and small-airways collapse during exhalation, leading to
so-called gas trapping, while goblet cell metaplasia and
impaired mucociliary function contribute to excess
mucus accumulation and worsening obstruction.
Smoking cessation
Preventing or limiting lung damage through smoking
cessation should be the foremost goal for all physicians
managing COPD. Of course, all smokers should be
encouraged to stop smoking, whether or not they have
COPD. Smoking cessation reduces rate of decline of FEV1
as well as improving respiratory symptoms and healthrelated quality of life. To date, smoking cessation and
home oxygen therapy (in severely hypoxaemic individuals) are the only strategies conclusively demonstrated to
improve mortality in COPD. Even brief counselling can
be effective. But additional strategies may be required for
patients who continue to smoke despite having lung
disease. All forms of nicotine replacement therapy (NRT)
appear to assist smoking cessation in dependent smokers,
and NRT is safe even in acute coronary syndromes.
Agents such as the antidepressant and selective
catecholamine reuptake inhibitor buproprion and the
42 nicotinic acetylcholine receptor partial agonist
varenicline are also effective. All pharmacologic therapies
must be combined with support and counselling for
maximum efficacy.26
Pharmacotherapy
The aims of pharmacotherapy in COPD are to relieve
symptoms (notably, breathlessness) and to prevent
deterioration, either by reducing exacerbations or by
reducing decline in quality of life, or both.
Bronchodilators remain the mainstay of therapy for
COPD and include short- and long-acting 2 agonists
(SABA and LABA) as well as short- and long-acting
muscarinic antagonists (SAMA and LAMA).They can
impact the gas trapping that is a feature of COPD, inducing improvements in inspiratory capacity and endexpiratory lung volume that may improve breathlessness
and exercise capacity even in the absence of a demonstrable bronchodilator response on simple spirometric
testing. In addition to improving symptom control, both
LAMA and LABA have been shown to reduce exacerbations and hospitalisations and to improve lung function.27
2013 The Authors
Internal Medicine Journal 2013 Royal Australasian College of Physicians
Advances in COPD
Newer therapies
Indacaterol is a novel ultra-LABA with 24-h bronchodilator efficacy allowing once-daily dosing. It may be
superior to conventional LABA in patients with moderate
to severe COPD and is comparable in efficacy with
tiotropium.29 The combination of indacaterol plus
tiotropium provides additional bronchodilation compared with each treatment alone.30 As understanding
of COPD inflammatory pathways increases, newer
therapies targeting inflammatory molecules have been
developed. Roflumilast, a selective phosphodiesterase-4
inhibitor, has recently been approved for use in several
countries for treatment of severe COPD (although not yet
in Australia). It has been shown to be effective, with
well-tolerated side effects,31 and may be suited for
patients with severe COPD and frequent exacerbations.32
However, long-term data on efficacy and adverse events
are not yet available, and its role in patients already
receiving standard combination therapy is yet to be determined.33 Although standard-dose theophylline is considered a third- or fourth-line treatment in COPD, low-dose
theophylline has recently been raised as a possible
adjunct to current inhaled therapies, given experimental
data demonstrating it enhances anti-inflammatory effects
of inhaled corticosteroids in COPD airways through
modification of histone deacetylase-2. Nonetheless,
large-scale clinical trials investigating exacerbation
reduction through this mechanism are awaited.34 Given
the known anti-inflammatory and immunomodulatory
effects of macrolide antibiotics, several studies have
evaluated their effects on reducing COPD exacerbations.
A recent study found a decreased rate of exacerbations in
patients treated with daily azithromcyin.35 Adverse
effects included ototoxicity and increased macrolide
2013 The Authors
Internal Medicine Journal 2013 Royal Australasian College of Physicians
Vaccination
Influenza vaccine reduces the number of acute exacerbations that occur in persons with COPD, but evidence
regarding its effects on hospitalisations and mortality is
inconclusive. Pneumococcal vaccine reduces the incidence of invasive pneumococcal disease, but there is a
lack of evidence concerning its effect on morbidity or
857
Oxygen therapy
The use of domiciliary oxygen is common at the more
severe end of the COPD spectrum. In 2005 21 000 Australians were receiving domiciliary oxygen therapy, at an
estimated annual cost of over A$32 million, with the
major indication being COPD.50 Long-term continuous
oxygen therapy has been proven to offer survival benefits
in patients with COPD and severe hypoxaemia (PaO2
55 mmHg or 5559 mmHg with evidence of end-organ
damage). However, the role of oxygen therapy in patients
with exertional desaturation, nocturnal hypoxaemia or
resting mild to moderate hypoxaemia is less clear. Recent
studies suggest an absence of long-term effects on breathlessness or quality of life from the use of ambulatory
oxygen therapy in normoxaemic or mildly hypoxaemic
patients with COPD who desaturate with exertion, even
though they may demonstrate small acute benefits
during laboratory-based exercise tests.51,52 Nonetheless,
occasional so-called n-of-1 trials may be of use in some
individuals.52 Isolated nocturnal hypoxaemia is not
uncommon in COPD patients, particularly during rapid
eye movement sleep. However, it has not been shown to
lead to worse quality of life, daytime hypoxaemia or
pulmonary hypertension. Limited studies have not consistently shown beneficial effects in sleep quality, pulmonary haemodynamics or survival over 2 years with
nocturnal supplemental oxygen.5355 Similarly, patients
with COPD and resting mild-to-moderate hypoxaemia
have not shown a survival benefit with domiciliary
oxygen therapy. The currently recruiting US Long-term
Oxygen Treatment Trial (NCT00692198) may provide
more data regarding the effects of domiciliary oxygen in
the latter patient subgroup.
2013 The Authors
Internal Medicine Journal 2013 Royal Australasian College of Physicians
Advances in COPD
Non-invasive ventilation:
acute versus stable
Non-invasive ventilation (NIV) is considered the standard
of care for patients with acute exacerbations of COPD
associated with hypercapnic respiratory failure and acidosis. It has been shown to reduce mortality, need for
intubation, treatment failure, treatment complications
and length of hospital stay.22 Patients who survive after
an episode of acute hypercapnic respiratory failure
treated with NIV are at high risk of readmission and
life-threatening events during the following year.
Although there are theoretical reasons why chronic NIV
may benefit such patients, results from randomised controlled trials have been conflicting. A systematic review
concluded there was no consistent clinically or statistically significant effect of domiciliary NIV on lung function, gas exchange, exercise tolerance, respiratory muscle
strength or sleep efficiency.56 However, many included
studies had small sample sizes, included patients without
significant hypercapnia, were of limited duration and/or
used low levels of inspiratory pressure support. An Australian study randomised 144 patients to receive home
NIV plus long-term home oxygen therapy versus oxygen
alone.57 Home NIV was associated with an improvement
in survival up to 3.5 years, at the expense of worse
quality of life. In summary, NIV may be a therapeutic
option in stable COPD patients with chronic ventilatory
failure, but further long-term randomised controlled
trials are awaited.
References
1 Australian Bureau of Statistics. National
Health Survey: summary of results,
20072008. [cited 2012 Nov 1].
Available from URL: http://www.abs
.gov.au/ausstats/abs@.nsf/mf/4364.0/
2 Buist AS, McBurnie MA, Vollmer WM,
Gillespie S, Burney P, Mannino DM
et al. International variation in the
prevalence of COPD (the BOLD Study):
a population-based prevalence study.
Lancet 2007; 370: 74150.
3 Australian Institute of Health and
Welfare. COPD (chronic obstructive
pulmonary disease). [cited 2012 Nov 1].
Available from URL: http://www.
aihw.gov.au/copd/
4 Lundbck B, Lindberg A, Lindstrm M,
Rnmark E, Jonsson AC, Jnsson E et al.
Not 15 but 50% of smokers develop
COPD? Report from the Obstructive
Lung Disease in Northern Sweden
Studies. Respir Med 2003; 97: 11522.
5 Zeng G, Sun B, Zhong N.
Non-smoking-related chronic obstructive
pulmonary disease a neglected entity?
Respirology 2012; 17: 90812.
6 Shirtcliffe P, Weatherall M, Marsh S,
Travers J, Hansell A, McNaughton A
et al. COPD prevalence in a random
population survey: a matter of
definition. Eur Respir J 2007; 30: 2329.
860
Conclusion
COPD is a common disease associated with significant
morbidity and mortality. Spirometry is key to its diagnosis
and is required in order to avoid under- and
overtreatment. Smoking cessation and oxygen therapy in
those who are hypoxaemic may reduce mortality.
Pharmacologic and non-pharmacologic therapy can
improve symptoms, quality of life and exercise capacity
and, through their effects on reducing exacerbations,
have the potential to modify disease progression.
Comorbidities are common and require targeted
treatment.
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