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Prevention of COPD
15
HyoungKyu Yoon
Introduction
Chronic obstructive pulmonary disease (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 lungs to noxious particles or gases
[1]. Chronic airway inflammation, which is a
pathogenic mechanism of COPD, is caused by
gene–environment interactions. Although the
genetic factors contributing to gene–environment
interactions cannot be controlled, COPD can be
prevented if the environmental risk factors are
eliminated. COPD prevention is more important
than treatment because it is almost impossible to
lung function normalization after airflow limitation occurs in COPD.
Rates of COPD have continuously increased
worldwide, as people become increasingly
exposed to COPD environmental risk factors,
especially in developing countries. Until now, the
majority of research and therapeutic interventions have focused on treating COPD after it
develops. There has been limited focus on COPD
prevention. Efforts to prevent COPD are lacking,
HK. Yoon
Yeouido St. Mary’s Hospital, The Catholic University
of Korea, Seoul, South Korea
e-mail: cmcyhg@catholic.ac.kr
particularly because they have not focused on
primary prevention.
Strategies used to prevent any chronic disease
can be divided into three stages: (1) primary prevention to suppress the occurrence of disease, (2)
secondary prevention to diagnose and treat a disease in its early stages, and (3) tertiary prevention
to treat a patient with a disease in progress so that
he or she can resume a normal life.
In the case of COPD, primary prevention
involves preventing healthy people from becoming exposed to COPD risk factors to prevent the
development of COPD. Primary prevention is the
most crucial aspect of COPD management. To
make an effective COPD prevention strategy, it is
necessary to clarify what a COPD risk factor is.
Among several risk factors, smoking is the most
important for COPD. Smoking prevention and
smoking cessation are central aspects of epidemiological measurements to counteract COPD
epidemics [2].
However, at least one-fourth of patients with
COPD are nonsmokers, and the burden of COPD
in nonsmokers is higher than previously believed
[3]. Risk factors for COPD in nonsmokers
include genetics, long-standing asthma, outdoor
air pollution (from traffic and other sources),
environmental smoke exposure, indoor air pollution such as biomass smoke, diet, recurrent respiratory infection in early childhood, tuberculosis,
and exposure to toxic gas or dust in the workplace. Indoor pollution, which is caused by using
biomass for heating and cooking in developing
© Springer-Verlag Berlin Heidelberg 2017
S.-D. Lee (ed.), COPD, DOI 10.1007/978-3-662-47178-4_15
211
212
countries, is a significant problem. Additional
causes of COPD include old age, low socioeconomic status, chronic bronchitis, airway hypersensitivity, and infection.
Preventive strategies are also important in
patients with established COPD. Continued
exposure to noxious agents promotes a more
rapid decline in lung function and increases the
risk of repeated exacerbations, eventually leading
to end-stage disease. Without major prevention
efforts, there will be an increasing proportion of
end-stage patients who can live longer through
long-term oxygen therapy and assisted ventilation, but with increased suffering and costs.
Therefore, secondary prevention, which involves
diagnosing COPD in its early stages and preventing constant exposure to risk factors, is also very
important. Indeed, preliminary research has
shown that early intervention based on minimizing these risk factors might be a cost-effective
way to prevent COPD.
The main point of tertiary prevention is to prevent death by COPD by controlling the rapid
decrease of lung function through proper treatment and by preventing acute exacerbation.
This chapter primarily discusses the primary
prevention of COPD and the use of spirometry
related to early diagnosis during secondary prevention. Tertiary prevention is about controlling
the progression of COPD and treatment related to
the prevention of acute exacerbation.
rimary Prevention: COPD Risk
P
Factors and Their Prevention
Interventions based on reducing exposure to
COPD risk factors are critical to strategies aimed
at preventing COPD. The most important way to
prevent COPD is to avoid smoking and reduce
exposure to toxic gases or dust in many ways,
such as via occupational exposure.
Smoking
The major risk factor for the development of
COPD is cigarette smoking, and 90% of deaths
HK. Yoon
due to COPD are directly attributable to smoking. It is well known that cigarette smoking
accounts for 80% of the total COPD burden.
Therefore, smoking cessation is the most effective means of halting or slowing the progress of
this disease.
Although previous studies suggested that
10–15% of smokers develop COPD, more recent
studies indicate that some degree of airflow limitation is present in up to 50% of smokers, with
clinically significant COPD being present in
approximately 25% of smokers [4]. Smoking
cessation is the most effective means of stopping
the progression of COPD as well as increasing
survival and reducing morbidity. This is why
smoking cessation should be the top priority in
the treatment of COPD [5]. Presently, quitting
smoking and home oxygen therapy are the only
ways to lower mortality rates among COPD
patients.
Smoking cessation can lead to primary, secondary, and tertiary prevention, so it is the most
important part of any COPD prevention strategy.
Encouraging people to quit smoking in order to
prevent further lung damage is the most important and valuable task and should be the most
important goal of all doctors who treat COPD. Of
course, this is true for all smokers, whether they
are COPD patients or not. However, many COPD
patients are unable to quit smoking. Smoking is
very common among COPD patients; 54–77% of
mild COPD patients and 38–51% of severe
COPD patients smoke [5]. In order to achieve a
reasonable quit rate, it is necessary to administer
behavioral support (e.g., counseling) in combination with pharmacological drugs [6].
Preventing or limiting lung damage through
smoking cessation should be the foremost goal of
all physicians managing COPD. Of course, all
smokers should be encouraged to stop smoking,
whether they have COPD or not. Smoking cessation reduces the rate of FEV1 decline and
improves respiratory symptoms and health-­
related quality of life.
Even brief counseling can be effective. All
doctors must ask their patients whether they
smoke and determine if they want to quit smoking, and smokers should be encouraged to quit.
15 Prevention of COPD
Of the various behavioral interventions available
that can increase the likelihood of smoking cessation, one of the simplest and most effective strategies that physicians can use is to simply advise
their patients to quit, particularly if this advice is
combined with information about the patient’s
“lung age” [7].
However, doctors should consider drug treatment to induce more effective smoking cessation
results. First-line pharmacological drugs used for
smoking cessation include nicotine-replacement
therapy (patches, gum, inhalers, nasal sprays, lozenge/tablets, and oral sprays), varenicline, and
bupropion SR. These drugs have scientific, well-­
documented efficacy when used for 2–3 months
[6, 8, 9]. All pharmacologic therapies must be
combined with support and counseling for maximum efficacy [10]. Verified quit rates at 12 months
of follow-up were 13.6 and 6.4% in the intervention and control groups, respectively. Thus, telling
smokers their lung age based on spirometry
results may increase the likelihood that they will
quit smoking [11].
Exposure to Biomass Smoke
It is increasingly recognized that a significant
proportion of patients with COPD are
nonsmokers.
This proportion is generally higher in developing countries, where exposure to biomass
smoke for heating and cooking is common (e.g.,
up to nearly 70% of people in India with COPD
are nonsmokers) [3], but it is also significant in
the developed world, with just under 40% of
people with COPD in a recent New Zealand
study being people who smoked and overall
international figures ranging from 25 to 45%
[12]. According to the World Health
Organization, approximately 50% of all households and 90% of rural households utilize biomass or coal fuels for cooking and heating in the
world. About three billion people worldwide are
exposed to smoke produced from biomass or
coal fuel burning [3].
According to the World Health Organization,
approximately 50% of all families and 90% of
213
families in rural areas use biomass or coal for
cooking and heating in developing countries.
About three billion people are affected by smoke
from biomass or coal combustion.
There are several ways to reduce indoor air
pollution exposure, such as by changing fuel type
or using an improved vented coal stove. Most of
all, recognition of indoor air pollution as a cause
of COPD is a key element of prevention.
Outdoor Air Pollution
According to longitudinal cohort studies, outdoor
air pollution is related to a decrease in lung function in children and adolescents [13, 14]. Therefore,
the risk of COPD can be increased upon exposure
to air pollution. This harmful effect of air pollution
may be caused by lung development impairment
during childhood. Several studies have indicated
that particulate pollution and nitrogen dioxide
(NO2) are significantly associated with impaired
lung development.
The two air pollutants that most commonly
exceed standards are ozone and particulate matter.
Ozone and particulate matter can harm anyone if
levels are sufficiently elevated, but health risks
from air pollution are greatest among vulnerable
populations. Both ozone and particulate matter
can cause pulmonary inflammation, decreased
lung function, and exacerbation of asthma.
Particulate matter is also strongly associated with
increased cardiovascular morbidity and mortality.
Children, older adults, and other vulnerable persons may be sensitive to lower levels of air pollution. For persons who are aware of local air
pollution levels, the seriousness of air pollution
(provided by a government agency) can be
checked on the Internet in real time. For avoiding
exposure to outdoor pollution, simple measures
can be taken; these include limiting the exertion
and time spent outdoors when air pollution levels
are highest and reducing the infiltration of outdoor air pollutants into indoor spaces [15].
In adults, higher levels of particulate matter
(<10 mm [PM10]) are negatively associated with
FVC, FEV1, and FEV1/FVC. Higher PM10 levels
are also correlated with an increased risk of COPD.
HK. Yoon
214
COPD acute exacerbation and symptoms
become worse when outdoor air pollution is high.
COPD patients should limit their outdoor activity, and younger people also needed to avoid
exposure to outside when air pollution levels are
high. The most effective solution is to reduce air
pollution, which will require more effort across
the country as well as international cooperation,
as pollution is not limited to the country; it is produced in and also influences nearby countries.
vitamin E, have good lung function, but the reasons for this are not clear. Many studies report
COPD “outbreaks” in obese patients although
many other studies have opposite findings [17].
The relationship between nutrition and COPD
prevention is not clear, but proper nutrition and
maintaining a normal weight lead to a better
prognosis in COPD patients.
Bronchial Asthma
Occupational Exposure
There is consistent evidence from population
studies that a median of 10–15% of the total burden of COPD is associated with exposure to
inhaled vapors, gases, dust, and fumes (VGDF)
in the workplace [16]. The evidence supporting
these risks varies. For example, the role of coal,
cadmium, silica, and biomass in COPD is relatively well established, and the role of more
generic exposure to potentially harmful inhaled
substances in the workplace is supported by evidence from a number of studies.
The causes of inorganic dust exposure are
welding, coal, coke, asphalt, silica, cement, tunnel work, cadmium, glass, bangle, and bleach.
The causes of organic dust are cotton, flax, jute,
farming, grain, and wood.
Control measures to prevent or reduce exposure
to VGDF in the workplace are the most effective
methods of reducing occupational COPD. However,
it is also important to diagnose COPD at the early
stage and in patients with rapidly decreasing lung
function. These individuals can be identified at
work by accurate annual assessments of lung function [16]. Lung function programs and health surveillance systems are needed for this purpose.
Workers in high-COPD-­
risk workplaces should
undergo regular examinations of lung function and
surveys of pulmonary symptoms.
Nutrition
Many studies have reported that people who eat a
diet high in antioxidants, such as vitamin C and
Asthma is associated with accelerated lung
function decline. This decline is greater in
smoking asthmatics. Low baseline lung function (FEV1% predicted), less reversibility to
β2-agonists, more severe bronchial hyperresponsiveness, mucus production, male sex, and
frequent exacerbations are associated with an
excess decline in FEV1 among persons with
asthma. Most studies indicated that irreversible
obstruction occurs in older patients with a longer duration of asthma; duration of asthma
appears to be more important than chronological age. Whether interventions designed to control tissue remodeling in asthma can prevent the
development of COPD is a question that needs
to be addressed.
Several studies have shown that childhood
asthma may be associated with abnormal lung
function in adults. Optimal control of bronchial
asthma, especially during childhood and adolescence, is important to prevent permanent impairment of lung function.
Risk Factors of Early Origin
There is growing evidence that COPD may begin
very early in life. It may be associated with lung
damage to the developing lung during the intrauterine period and the first few years of postnatal
life, when lung growth and development are
rapid. Early-life risk factors may include fetal
and early infant growth patterns; preterm birth;
maternal obesity, diet, and smoking; the child’s
diet; allergen exposure; respiratory tract infections; and genetic susceptibility [18]. The most
15 Prevention of COPD
important risk factor for chronic obstructive lung
diseases in childhood is maternal tobacco smoking [19].
Recently, information about early-life risk
factors has become more accessible, but people
do not know how big this influence is, and there
is no effective prevention. However, it will be
very important to identify those individuals who
are exposed to these risk factors early in life in
order to begin proper observation and treatment.
Furthermore, physicians need to recognize that
lung disease is potentially associated with early-­
life insults and provide better education regarding diet, exercise, and the avoidance of smoking
to preserve the precious reserves of lung function
in susceptible adults [20].
Secondary Prevention
Early Detection: Spirometry
According to the Lung Health Study (LHS), lack
of awareness and knowledge about COPD among
healthcare providers is an important factor in
misdiagnosis and/or delays in diagnosis. Major
overhauls in both cultural and primary care settings are needed to achieve the goal of early
COPD diagnosis. Extensive innovation and
changes are needed in primary treatment to diagnose COPD in its early stages. Spirometry is a
method commonly used to diagnose early-stage
COPD. Medical personnel should be educated to
perform spirometry when smokers older than
40 years show respiratory symptoms [21].
The LHS showed that spirometry can be successfully used to assess smoking cessation as a
means to prevent COPD progression [22].
According to recent research, spirometry can
effectively encourage patients to quit smoking,
especially those whose spirometry results show
respiratory obstruction [23]. However, in other
studies, public spirometry not with high-risk
groups did not effectively encourage people to
quit smoking. However, there are limitations to
these findings, as many young people were
included as a target group in this research. There
is no definite evidence showing that public
215
s­pirometry in smokers older than 40 years
increases the possibility that a person will quit
smoking or identifies early-stage COPD patients.
Smoking Cessation in COPD Patients
The LHS, a 5-year early intervention study combining behavioral therapy and nicotine gum versus standard care in 3926 smokers with
mild-to-moderate airflow limitation due to
COPD, demonstrated that participants who quit
smoking and remained abstinent had improved
FEV1 in the year after quitting smoking and demonstrated a subsequent age-related decline in
FEV1 that was half the rate of continuing smokers
[24]. This benefit of sustained smoking cessation
in slowing the rate of progressive lung function
loss to a level comparable to that of never-­
smokers persisted for at least an additional
6 years among the quitters who remained
­abstinent [7].
Brief advice and spirometry are effective to
support smoking cessation in COPD patients. In
one study, subjects were made to underwent
spirometry and were given smoking cessation
­
advice by a nurse and a letter from a physician
reinforcing the results of their spirometry annually
for 3 years. After various exclusions, of those
remaining in the study after 3 years, 25% of
­smokers with COPD at baseline had been smoke-­
free for 1 year compared to 7% of those smokers
with normal lung function who received the same
level of intervention [25]. In a separate analysis of
data from the LHS, a reduction in the number of
cigarettes smoked per day in the absence of complete cessation did not influence the rate of decline
in lung function unless the percentage reduction
was very marked (>85%), a degree that was
achieved by only a small minority of subjects [26].
When COPD patients quit smoking, infection causing acute exacerbation and a decrease
in lung function occurs at lower rates.
Additionally, COPD patients who quit smoking
consistently show reasonable decreases in allcause mortality, cardiovascular disease, lung
cancer, coronary heart disease, and death due to
other factors [27].
HK. Yoon
216
Tertiary Prevention
tions could be more effective in early disease
than in late disease [30].
Prevention of Disease Progression
COPD is a heterogeneous disease. As shown in
the ECLIPSE study, the speed of decrease in lung
function varies among patients, such that one
patient can show almost no decrease in lung
function while another patient shows a rapid
decrease. Tertiary prevention of COPD involves
controlling this decrease of lung function by finding the causes of the rapid decrease in lung function and providing active treatment that is
designed for end-stage COPD. It is very important to discover biomarkers to help identify this
rapid-decliner group early. To discover this biomarker, it is necessary to use diverse methods,
such as spirometry and chest computed tomography scan and to assess airway hyperreactivity,
health status, physical activity, and comorbidity.
The proper treatment of COPD phenotypes has
not been identified, but phenotypic-specific treatment will be a crucial aspect of COPD tertiary
prevention in the future.
Smoking cessation is the most crucial and
effective method to control the speed of lung
function decline in COPD patients. Therefore, all
COPD patients must not smoke, regardless of the
severity of COPD.
Several large randomized controlled studies
[22, 28, 29], suggest that disease progression can
be slowed in established COPD. In the TORCH
study, spirometry also showed significantly
reduced progression with fluticasone propionate
(13 mL/year), salmeterol (13 mL/year), and the
combination (16 mL/year) compared with placebo although these differences are less than the
generally accepted clinical target of 20 mL/year.
The UPLIFT study reported no significant difference in lung function decline between patients
given tiotropium and those given placebo.
However, among individuals with moderate disease, the rate of FEV1 loss among those given
tiotropium was 6 mL less than that of controls.
Although not tested for primary or secondary
prevention, these findings suggest that, as with
smoking cessation, pharmacological interven-
Prevention of Acute Exacerbation
Acute exacerbation represents the biggest portion
of the socioeconomic cost of COPD treatment.
Additionally, acute exacerbations reduce quality
of life and lung function and can even cause
death. Therefore, prevention of COPD acute
exacerbation is very important in tertiary
prevention.
Influenza vaccine reduces approximately 37%
of the total number of exacerbations per patient
compared with placebo because vaccination prevents late exacerbation after 3–4 weeks [31].
However, 23 valent pneumococcal vaccines cannot prevent acute exacerbation and reduce the
number of deaths due to COPD.
According to a large randomized controlled
study, long-acting в agonist (LABA) or long-­
acting antimuscarinic (LAMA) bronchodilators
and inhaled corticosteroid-LABA combinations
prevent exacerbation. Triple therapy with inhaled
corticosteroid-LABA plus LAMA shows an
additional prevention effect. Antibiotics such as
PDE4 inhibitors and azithromycin can also prevent exacerbation. Strong evidence indicates that
daily variation in exposure to outdoor air pollution is correlated with acute exacerbations of
COPD.
References
1. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier
C, Anzueto A, et al. Global strategy for the diagnosis,
management, and prevention of chronic obstructive
pulmonary disease: GOLD executive summary. Am
J Respir Crit Care Med. 2013;187(4):347–65.
2.Viegi G, Pistelli F, Sherrill DL, Maio S, Baldacci S,
Carrozzi L. Definition, epidemiology and natural history of COPD. Eur Respir J. 2007;30(5):993–1013.
3.Zeng G, Sun B, Zhong N. Non-smoking-related
chronic obstructive pulmonary disease: a neglected
entity? Respirology. 2012;17(6):908–12.
4.Lundback B, Lindberg A, Lindstrom M, Ronmark
E, Jonsson AC, Jonsson E, et al. Not 15 but 50% of
smokers develop COPD?—report from the o­ bstructive
15 Prevention of COPD
lung disease in northern Sweden studies. Respir Med.
2003;97(2):115–22.
5.Tonnesen P. Smoking cessation and COPD. Eur
Respir Rev. 2013;22(127):37–43.
6.Stead LF, Perera R, Bullen C, Mant D, Hartmann-­
Boyce J, Cahill K, et al. Nicotine replacement therapy
for smoking cessation. Cochrane Database Syst Rev.
2012;11:CD000146.
7.Tashkin DP, Murray RP. Smoking cessation in
chronic obstructive pulmonary disease. Respir Med.
2009;103(7):963–74.
8.Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane
Database Syst Rev. 2012;4:CD006103.
9.Hughes JR, Stead LF, Lancaster T. Antidepressants
for smoking cessation. Cochrane Database Syst Rev.
2007;1:CD000031.
10.
McDonald CF, Khor Y. Advances in chronic
obstructive pulmonary disease. Intern Med
J. 2013;43(8):854–62.
11.Parkes G, Greenhalgh T, Griffin M, Dent R. Effect
on smoking quit rate of telling patients their lung
age: the Step2quit randomised controlled trial. BMJ.
2008;336(7644):598–600.
12. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9691):733–43.
13.Rojas-Martinez R, Perez-Padilla R, Olaiz-Fernandez
G, Mendoza-Alvarado L, Moreno-Macias H, Fortoul
T, et al. Lung function growth in children with long-­
term exposure to air pollutants in Mexico City. Am
J Respir Crit Care Med. 2007;176(4):377–84.
14.Gauderman WJ, Avol E, Gilliland F, Vora H, Thomas
D, Berhane K, et al. The effect of air pollution on
lung development from 10 to 18 years of age. N Engl
J Med. 2004;351(11):1057–67.
15.Laumbach RJ. Outdoor air pollutants and patient
health. Am Fam Physician. 2010;81(2):175–80.
16. Fishwick D, Sen D, Barber C, Bradshaw L, Robinson
E, Sumner J, et al. Occupational chronic obstructive
pulmonary disease: a standard of care. Occup Med
(Lond). 2015;65(4):270–82.
17.
Hanson C, Rutten EP, Wouters EF, Rennard
S. Influence of diet and obesity on COPD development and outcomes. Int J Chron Obstruct Pulmon Dis.
2014;9:723–33.
18.Duijts L, Reiss IK, Brusselle G, de Jongste JC. Early
origins of chronic obstructive lung diseases across the
life course. Eur J Epidemiol. 2014;29(12):871–85.
19. Neuman A, Hohmann C, Orsini N, Pershagen G, Eller
E, Kjaer HF, et al. Maternal smoking in pregnancy
and asthma in preschool children: a pooled analysis
of eight birth cohorts. Am J Respir Crit Care Med.
2012;186(10):1037–43.
217
20.Stocks J, Sonnappa S. Early life influences on the
development of chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2013;7(3):161–73.
21.Jagana R, Bartter T, Joshi M. Delay in diagnosis of
chronic obstructive pulmonary disease: reasons and
solutions. Curr Opin Pulm Med. 2015;21(2):121–6.
22.Anthonisen NR, Connett JE, Kiley JP, Altose MD,
Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic
bronchodilator on the rate of decline of FEV1. The
Lung Health Study. JAMA. 1994;272(19):1497–505.
23.Bednarek M, Gorecka D, Wielgomas J, Czajkowska-­
Malinowska M, Regula J, Mieszko-Filipczyk G, et al.
Smokers with airway obstruction are more likely to
quit smoking. Thorax. 2006;61(10):869–73.
24.Scanlon PD, Connett JE, Waller LA, Altose MD,
Bailey WC, Buist AS, et al. Smoking cessation and
lung function in mild-to-moderate chronic obstructive pulmonary disease. The lung health study. Am
J Respir Crit Care Med. 2000;161(2 Pt 1):381–90.
25.Stratelis G, Molstad S, Jakobsson P, Zetterstrom
O. The impact of repeated spirometry and smoking
cessation advice on smokers with mild COPD. Scand
J Prim Health Care. 2006;24(3):133–9.
26.Simmons MS, Connett JE, Nides MA, Lindgren PG,
Kleerup EC, Murray RP, et al. Smoking reduction and
the rate of decline in FEV(1): results from the lung
health study. Eur Respir J. 2005;25(6):1011–7.
27.Anthonisen NR, Skeans MA, Wise RA, Manfreda
J, Kanner RE, Connett JE, et al. The effects of a
smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med.
2005;142(4):233–9.
28.Decramer M, Celli B, Kesten S, Lystig T, Mehra S,
Tashkin DP, et al. Effect of tiotropium on outcomes
in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup
analysis of a randomised controlled trial. Lancet.
2009;374(9696):1171–8.
29.Celli BR, Thomas NE, Anderson JA, Ferguson
GT, Jenkins CR, Jones PW, et al. Effect of pharmacotherapy on rate of decline of lung function in
chronic obstructive pulmonary disease: results from
the TORCH study. Am J Respir Crit Care Med.
2008;178(4):332–8.
30.Rennard SI, Drummond MB. Early chronic obstructive pulmonary disease: definition, assessment, and
prevention. Lancet. 2015;385(9979):1778–88.
31.Poole PJ, Chacko E, Wood-Baker RW, Cates
CJ. Influenza vaccine for patients with chronic
obstructive pulmonary disease. Cochrane Database
Syst Rev. 2006;1:CD002733.
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