30/08/2023, 08:53 Role of inhaled glucocorticoid therapy in stable COPD - UpToDate

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Papel da terapia com glicocorticóides inalados na DPOC

estável
AUTOR: James K Stoller, MD, MS
EDITOR DE SEÇÃO: Peter J Barnes, DM, DSc, FRCP, FRS
EDITOR ADJUNTO: Paul Dieffenbach, MD

Todos os tópicos são atualizados à medida que novas evidências são disponibilizadas e nosso processo de revisão por
pares é concluído.

Revisão da literatura atualizada até:  julho de 2023.

Última atualização deste tópico:  16 de maio de 2023.

INTRODUÇÃO

A doença pulmonar obstrutiva crônica (DPOC) é uma doença inflamatória caracterizada por
inflamação das vias aéreas e sistêmica [ 1 ]. A terapia com glicocorticóide inalado (também
chamado de corticosteróide inalado ou ICS) parece reduzir essa inflamação [ 2–6 ]. Assim,
levantou-se a hipótese de que a terapia com ICS também pode melhorar os resultados
clínicos.

As evidências clínicas de que a terapia com CI é benéfica para a maioria dos pacientes com
DPOC são limitadas. Apesar disso, 40 a 50 por cento dos pacientes com DPOC recebem
terapia com CI [ 7,8 ]. Entre as razões para o uso generalizado da terapia com CI estão o
reconhecimento de que a DPOC pode ter um componente asmático e ensaios que
demonstram o benefício do CI em adição à terapia broncodilatadora dupla em pacientes
com DPOC moderada a grave e exacerbações frequentes [9,10 ] . No entanto, o uso
inadequado de CI como parte da terapia inicial também é comum [ 11 ].

Nesta revisão de tópico, são discutidas a eficácia clínica e a abordagem da terapia com CI em
pacientes com DPOC. Os efeitos adversos dos glicocorticóides inalados são discutidos com
mais detalhes separadamente. O manejo farmacológico da DPOC estável e o papel dos
glicocorticóides sistêmicos nas exacerbações da DPOC também são apresentados
separadamente.

● (Consulte "Principais efeitos colaterais dos glicocorticóides inalados" .)

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Role of inhaled glucocorticoid therapy in stable COPD - UpToDate

● (Consulte "DPOC estável: manejo farmacológico inicial" .)

● (Consulte "DPOC estável: manejo farmacológico de acompanhamento" .)

● (Consulte "Exacerbações da DPOC: Tratamento" .)

EFICÁCIA CLÍNICA

Muitos estudos examinaram o impacto dos glicocorticóides inalados (ICS) na função

pulmonar, sintomas respiratórios, exacerbações, mortalidade, câncer de pulmão e
inflamação das vias aéreas em pacientes com DPOC. Esses estudos relataram dados
conflitantes para vários resultados diferentes. No entanto, em conjunto, os dados sugerem
que a terapia com CI tem um impacto mínimo na função pulmonar, mas diminui as
exacerbações, retarda modestamente a progressão dos sintomas respiratórios e pode
melhorar marginalmente a mortalidade por DPOC.

Função pulmonar  —  O impacto da terapia com CI na progressão da doença, conforme

medido pela taxa anual de declínio do volume expiratório forçado no primeiro segundo (VEF
1 ) , foi examinado em vários ensaios randomizados e três meta-análises [ 12-19 ]. O maior
ensaio randomizado [ 20 ] e uma meta-análise descobriram que a terapia com ICS retardou
ligeiramente o declínio da função pulmonar, enquanto vários outros estudos e uma meta-
análise diferente não encontraram nenhum efeito benéfico na função pulmonar. Como
exemplos:

● Ensaio TORCH – O ensaio Toward a Revolution in COPD Health (TORCH) designou

aleatoriamente 6.112 pacientes com DPOC moderada a grave – o VEF 1 médio foi de 44
por cento do previsto – para um dos quatro braços de tratamento durante três anos:
salmeterol sozinho (50 mcg duas vezes ao dia ), fluticasona sozinha (500 mcg duas
vezes ao dia), terapia combinada (salmeterol mais fluticasona) ou placebo [ 16,20 ].
Todos os tratamentos ativos retardaram o declínio da função pulmonar em comparação
com o placebo, incluindo a fluticasona (-55 versus -42 mL por ano). A importância clínica
desta pequena diferença é desconhecida.

● In a meta-analysis of trials longer than two years that included the TORCH trial, the
mean difference in the rate of decline in postbronchodilator FEV1 between ICS and
placebo was 7.3 mL/year (95% CI 3.2-11.4 mL/year, 12,502 participants) [19].

The reason for the conflicting data is uncertain but may be a function of different doses and
formulations of inhaled glucocorticoids, length of study, or other confounding factors that
influence studies over longer periods of time.

Symptoms — Respiratory symptoms were predetermined secondary outcomes in four out of

the five randomized trials and one of the meta-analyses [12,14-16,19]. Most demonstrated
th t ICS th l d th i f i t t d tl [14 16] lth
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that ICS therapy slowed the progression of respiratory symptoms modestly [14-16], although

one trial found that ICS therapy had no impact on respiratory symptoms [12]. ICS slowed the
rate of decline in quality of life compared with placebo, as measured by a standard
respiratory disease questionnaire, although the mean difference was not clinically
meaningful [19].

Exacerbations — Glucocorticoid-responsive inflammatory factors appear to play an

important role in the initiation and severity of exacerbations of COPD. Thus, it has been
hypothesized that ICS therapy may prevent or reduce the severity of COPD exacerbations.
Many studies support this theory [9,10,14-16,19,21-25], as illustrated by the following:

● A systematic review and meta-analysis demonstrated that ICS therapy decreased the
relative risk of exacerbations compared with placebo (rate ratio 0.88; 95% CI, 0.82-0.94,
10,097 participants); most patients were on background single-agent bronchodilator
therapy [19]. Three other meta-analyses reported similar results [21,23,25].

● The TORCH trial (n = 6112) described above demonstrated that ICS therapy decreased
the rate of moderate or severe exacerbations (rate ratio [RR] 0.82; 95% CI, 0.76-0.89)
and the rate of exacerbations requiring systemic glucocorticoids (RR 0.65; 95% CI, 0.58-
0.73) compared with placebo [16]. However, it did not reduce the rate of severe
exacerbations that required hospitalization and its statistical methods have been
criticized [26].

● The IMPACT, ETHOS, and TRIBUTE trials each compared a single, once-daily inhaler
containing inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting
muscarinic antagonist (LAMA) with a combined LABA-LAMA inhaler and other therapies.
The annualized rate of moderate to severe exacerbations in the ICS-LAMA-LABA group
was lower than with LAMA-LABA alone in each of the three trials (with an absolute
improvement ranging from approximately 0.1 to 0.3 per year, RR approximately 0.80).
In IMPACT, hospitalizations due to exacerbations were also less frequent (0.13 versus
0.19 per year, RR 0.66). (See "Stable COPD: Follow-up pharmacologic management",
section on 'Exacerbations on LAMA-LABA therapy'.)

Post-hoc analyses of these and other trials reveal some evidence that the benefits of inhaled
glucocorticoids accrue to patients with higher rather than lower markers of eosinophilic
inflammation.

● In one post-hoc analysis of three trials of budesonide-formoterol versus formoterol

alone (n = 4528), the presence of eosinophils was associated with decreased
exacerbations in the budesonide-formoterol group [27]. Patients with eosinophils >100
cells/microL experienced a 25 percent relative risk reduction compared with patients
with fewer than 100 eosinophils/microL; the risk reduction was 50 percent for those
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with eosinophils >340 cells/microL. Similar results were seen with beclomethasone in
the FORWARD study [28].

● Blood eosinophil count appeared similarly important in inhaled glucocorticoid efficacy

in post-hoc analyses of trials assessing inhaled ICS-LAMA-LABA combined inhaler
therapy [29-32]. For example, in IMPACT, the relative rate reduction in moderate to
severe exacerbations with ICS-LAMA-LABA compared with LABA-LAMA alone was 0.88 in
patients with a blood eosinophil count <90 cells/microL compared with 0.56 in patients
with a blood eosinophil count >310 cells/microL [31]. Improvements in lung function by
FEV1 were similarly eosinophil-dependent in other large trials of triple inhaler therapy
(KRONOS and ETHOS) [30,32].

Despite the benefits of inhaled glucocorticoids for patients with moderate to severe COPD,
there is also evidence that withdrawal of inhaled glucocorticoids is reasonable in many
patients. In the Withdrawal of Inhaled Steroids During Optimized bronchodilator
Management (WISDOM) trial, 2485 patients with moderate or severe COPD were treated with
triple therapy (tiotropium, salmeterol, and fluticasone, 500 mcg twice daily) for six weeks and
then randomly assigned to withdraw fluticasone over 12 weeks or continue triple therapy
with ongoing follow-up for 12 months [33]. Comparing withdrawal of ICS with continuation,
the hazard ratio (HR) of a first moderate or severe exacerbation of COPD was 1.06 (95% CI
0.94-1.19). Withdrawal was also associated with a small decrement (mean 38 mL at 18 weeks)
in FEV1. Similarly, in the DACCORD observational study, clinicians successfully identified 292
patients as good candidates for a switch from LAMA/LABA/ICS to LAMA/LABA [34]. Compared
with 675 patients who remained on LAMA/LABA/ICS therapy, fewer patients who switched
had exacerbations or worsening in COPD symptoms (33 versus 56 percent).

Patients most likely to benefit from inhaled glucocorticoids are those with exacerbations
refractory to other inhaled therapies or elevated eosinophil levels; however, a broader subset
of patients with COPD are often inappropriately prescribed these agents. The WISDOM trial,
along with the availability of newer inhaled bronchodilator treatment options, supports
withdrawal of inhaled glucocorticoids in selected COPD patients while monitoring for clinical
worsening. (See "Stable COPD: Follow-up pharmacologic management", section on
'Pharmacologic adjustment based on assessment'.)

Mortality — ICS therapy likely has a modest impact on COPD mortality, with some evidence
that this is driven by a subset of patients with severe disease, frequent exacerbations, and
increased eosinophilic inflammation. In a meta-analysis of 60 randomized trials including
over 100,000 patients, inhaled glucocorticoids resulted in a small mortality benefit compared
with nonglucocorticoid-containing regimens (odds ratio [OR] 0.90, 95% CI 0.84-0.97) [35].
Certain subgroups experienced a greater benefit, including patients with blood eosinophil
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counts >200 cells/microL (OR 0.58) or >2 percent on the differential (OR 0.61) and patients
with two or more moderate to severe exacerbations (OR 0.63).

As one example of a trial that contributed to this analysis, the IMPACT trial compared ICS-
LAMA-LABA therapy (fluticasone furoate-umeclidinium-vilanterol) with a once-daily LAMA-
LABA inhaler (umeclidinium-vilanterol) or a once-daily glucocorticoid-LABA inhaler
(fluticasone furoate-vilanterol) in 10,355 patients with COPD who were at increased risk of
exacerbations due to a combination of disease severity and exacerbation history [9]. After
nearly complete collection of records, there were deaths in 2.4 percent of patients in the
triple therapy group, 2.6 percent of patients in the LABA-ICS group, and 3.2 percent of
patients in the LABA-LAMA group [36]. The hazard ratio for triple therapy versus
umeclidinium–vilanterol was 0.72 (95% CI, 0.53-0.99). Other large trials included in the meta-
analysis, such as TORCH and ETHOS [10,16], showed similar trends towards improved
mortality with some ICS-combination therapies [9,10,36,37].

In addition to this evidence from randomized trials, one population-based cohort study
compared 5594 new users of a combination ICS-LABA with 2129 new users of a LABA alone
[38]. All users were age 66 years or older and met a case definition of COPD. New use of
LABAs and ICS was associated with a slightly reduced risk of death compared with new use of
LABAs alone (HR 0.92, 95% CI 0.87-0.97).

Lung cancer — Conflicting data have been presented about whether ICS protects against
lung cancer in patients with COPD. While observational studies suggested a protective effect
[39,40], a systematic review identified four randomized trials (10,200 participants with COPD)
that found no significant effect on lung cancer risk [13,15,16,41,42]. Methodologic issues,
such as dose, duration, and adherence to ICS treatment and low rates of lung cancer, limit
the conclusions that can be made, but data do not support use of ICS to reduce lung cancer
risk in COPD.

ADVERSE EFFECTS

Inhaled glucocorticoid therapy has a few well-described adverse effects in patients with
chronic obstructive pulmonary disease (COPD). They include dysphonia, skin bruising, and
oral candidiasis [13,15,43]. In general, these effects have not been severe enough to alter
management but appear to increase at higher doses and with cumulative exposure. There is
also accumulating data for an increased risk of lung infection in patients receiving ICS
therapy [9,10]. Additional adverse effects, such as subcapsular cataracts, diminished bone
density, and hypothalamic-pituitary-adrenal axis suppression, are suspected, but data are
conflicting, or the occurrence is less common. A more detailed discussion of adverse effects
associated with inhaled glucocorticoids is provided separately (See "Major side effects of
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associated with inhaled glucocorticoids is provided separately. (See Major side effects of
inhaled glucocorticoids".)

GENERAL APPROACH

Pharmacologic therapy for stable COPD is based on a stepwise approach in which inhaled
bronchodilators (beta agonists and muscarinic antagonists) are given alone, in combination,
or with the addition of inhaled glucocorticoids (ICS) ( algorithm 1). The goals of this
approach are to control symptoms, decrease exacerbations, and improve patient function
and quality of life. ICS therapy is not recommended as monotherapy for patients with stable
COPD, because inhaled bronchodilators have greater benefits with fewer adverse effects.
COPD patients being considered for treatment with inhaled glucocorticoids will usually have
moderate to severe airflow obstruction. (See "Stable COPD: Initial pharmacologic
management" and "Stable COPD: Follow-up pharmacologic management".)

Nonpharmacologic therapies (eg, smoking cessation, pulmonary rehabilitation, vaccination,

nutrition) should be initiated along with pharmacotherapy. (See "Stable COPD: Overview of
management".)

Patient selection

● Addition of ICS based on symptoms and exacerbations – ICS therapy is indicated as

an additional therapy for patients with COPD who have symptoms, repeated
exacerbations, or severe exacerbations despite an optimal inhaled bronchodilator
regimen, typically a long-acting muscarinic antagonist (LAMA) and a long-acting beta-
agonist (LABA). This is based on the observation that for patients with moderate to very
severe COPD, triple therapy (LAMA-LABA-ICS) decreases exacerbations compared with
dual therapy without an ICS [9,10].

● Addition of ICS based on blood eosinophils – For patients using a single

bronchodilator who have one COPD exacerbation a year and a blood eosinophil count
≥300 cells/microL, the Global Initiative for Chronic Obstructive Lung Disease (GOLD)
strategy suggests consideration of LAMA-LABA-ICS combination as an alternative to a
LAMA-LABA combination ( algorithm 1) [44]. Conversely, lower levels of blood
eosinophils (eg, <100 cells/microL) predict a low likelihood of response to ICS. For
patients with frequent exacerbations of COPD despite combined LAMA-LABA and blood
eosinophils ≥100 cells/microL, the GOLD strategy recommends changing to triple
therapy with LAMA-LABA-ICS, which is associated with a reduced rate of exacerbations
( table 1). Patients with frequent exacerbations despite LAMA-LABA therapy and
eosinophils <100 cells/microL may benefit from alternative therapies, typically
roflumilast or azithromycin. The studies in support of this approach are described
separately. (See "Stable COPD: Initial pharmacologic management", section on 'Group E
patients presenting with elevated eosinophil counts or hospitalization' and "Stable
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COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled

corticosteroids, and exacerbations' and "Stable COPD: Follow-up pharmacologic

management", section on 'Exacerbations on LAMA-LABA therapy'.)

● Asthma and COPD overlap – An inhaled glucocorticoid may be warranted earlier (ie, at
the same time that the long-acting inhaled bronchodilator is initiated) if there are signs
of an asthmatic component to the COPD. (See "Asthma and COPD overlap (ACO)".)

Dose — The optimal formulation, dose, and schedule of ICS for COPD are unknown. Several
of the large clinical trials evaluating the impact of ICS in patients with COPD have used
relatively high doses of ICS, including budesonide at 400 mcg twice daily or fluticasone at 500
mcg twice daily [13,14,16]. Although small clinical benefits were achieved at these doses,
adverse systemic effects were also detected (eg, cataracts, possible pneumonia) [16,45].
Subsequent trials, such as ETHOS and IMPACT, demonstrated benefit when a moderate ICS
dose (eg, budesonide 160 mcg and 320 mcg twice daily; fluticasone furoate 100 mcg once
daily) was added to dual bronchodilator therapy [9,10]. In our practice, we use low to
moderate doses of ICS unless the patient has asthma and COPD overlap; we increase the
dose of ICS if needed in patients who continue to have exacerbations.

Systemic glucocorticoid response not predictive of ICS response — It has been

hypothesized that patients with COPD who respond favorably to a course of systemic
glucocorticoids are more likely to benefit from ICS therapy. There is little evidence to support
this theory; thus, selection of patients based on their response to a trial of systemic
glucocorticoid therapy is not recommended.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Chronic obstructive
pulmonary disease".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
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comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Inhaled corticosteroid medicines (The Basics)")

● Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary
disease (COPD) (Beyond the Basics)" and "Patient education: Chronic obstructive
pulmonary disease (COPD) treatments (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Role of inhaled glucocorticoids in COPD – In patients with chronic obstructive

pulmonary disease (COPD), inhaled glucocorticoids (also known as inhaled
corticosteroids or ICS) have minimal impact on lung function, but decrease
exacerbations, modestly slow the progression of respiratory symptoms, and may mildly
improve COPD mortality. (See 'Clinical efficacy' above.)

● Adverse effects of inhaled glucocorticoids – Adverse effects of ICS therapy include

dysphonia, skin bruising, and oral candidiasis. These adverse effects appear to be more
common at higher doses. In addition, ICS therapy may increase the incidence of
pneumonia, increase the incidence of cataracts, and diminish bone density. (See
'Adverse effects' above.)

● Inhaled glucocorticoids as a component of stepwise therapy – Pharmacologic

therapy for stable COPD is based on a stepwise approach in which inhaled
bronchodilators (beta agonists and muscarinic antagonists) are given alone, in
combination, or with the addition of ICS ( algorithm 1 and table 1). The goals of
this approach are to control symptoms, decrease exacerbations, and improve patient
function and quality of life. (See 'General approach' above and "Stable COPD: Initial
pharmacologic management".)

● Potential indications for ICS – Patients who have persistent symptoms, repeated
exacerbations, or severe exacerbations despite a dual long-acting inhaled
bronchodilator regimen are good candidates for the addition of ICS therapy. (See
'Patient selection' above.)

● Use of peripheral eosinophils to guide ICS initiation – Analysis of multiple trials

including ICS therapy in COPD suggest that efficacy shows good correlation to the
degree of peripheral eosinophilia. For both initiation and follow-up therapy, the Global
Initiative for Chronic Obstructive Lung Disease (GOLD) strategy suggests peripheral
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eosinophil thresholds of ≥300 cells/microL and <100 cells/microL to delineate patients

likely to benefit and unlikely to benefit, respectively, from the addition of ICS to dual
bronchodilator (LAMA-LABA) therapy ( algorithm 1 and table 1). (See 'Patient
selection' above and "Stable COPD: Follow-up pharmacologic management", section on
'Blood eosinophils, inhaled corticosteroids, and exacerbations'.)

● Asthma and COPD – Inhaled glucocorticoid therapy may be warranted earlier (ie, at the
same time that the long-acting inhaled bronchodilator is initiated) if there are signs of
an asthmatic component to the COPD. (See 'General approach' above and "Asthma and
COPD overlap (ACO)".)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Marcia Erbland, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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disease: a randomized trial. Ann Intern Med 2007; 146:545.
23. Gartlehner G, Hansen RA, Carson SS, Lohr KN. Efficacy and safety of inhaled
corticosteroids in patients with COPD: a systematic review and meta-analysis of health
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24. Macie C, Wooldrage K, Manfreda J, Anthonisen NR. Inhaled corticosteroids and mortality
in COPD. Chest 2006; 130:640.
25. Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Inhaled corticosteroids vs placebo for
preventing COPD exacerbations: a systematic review and metaregression of randomized
controlled trials. Chest 2010; 137:318.
26. Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 173:842.

27. Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response
to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc
analysis of three randomised trials. Lancet Respir Med 2018; 6:117.
28. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood Eosinophils: A Biomarker of Response to
Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. Am J
Respir Crit Care Med 2015; 192:523.
29. Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual
bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-
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30. Rabe KF, Martinez FJ, Singh D, et al. Improvements in lung function with
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31. Pascoe S, Barnes N, Brusselle G, et al. Blood eosinophils and treatment response with
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32. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with
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versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-
blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir
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and exacerbations of COPD. N Engl J Med 2014; 371:1285.
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34. Vogelmeier CF, Worth H, Buhl R, et al. Impact of switching from triple therapy to dual
bronchodilation in COPD: the DACCORD 'real world' study. Respir Res 2022; 23:109.
35. Chen H, Deng ZX, Sun J, et al. Association of Inhaled Corticosteroids With All-Cause
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37. Martinez FJ, Rabe KF, Ferguson GT, et al. Reduced All-Cause Mortality in the ETHOS Trial
of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A
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lung cancer in patients with COPD? A systematic review. Respirology 2017; 22:61.
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44. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Di
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45. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of
cataracts. N Engl J Med 1997; 337:8.
Topic 1449 Version 37.0

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GRAPHICS

Novo diagnóstico de DPOC

COPD: chronic obstructive pulmonary disease; COVID-19: coronavirus disease 2019; GOLD: Global Initiati
CAT: COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic antagonist;
(anticholinergic); LABA: long-acting beta-agonist; mMRC: Modified Medical Research Council; FEV1: forced
forced vital capacity.

* COPD is diagnosed based on the presence of chronic respiratory symptoms (dyspnea, cough, sputum p
limitation. All patients with COPD defined by GOLD have airflow limitation based on a reduced FEV1/FVC r
is determined by the reduction in FEV1.

¶ An exacerbation of COPD is characterized by increased dyspnea and/or cough and sputum that worsen
accompanied by tachypnea or tachycardia, and is often caused by infection, environmental irritation, or o
exacerbations" are typically defined as those which require treatment with systemic glucocorticoids. Mor
been proposed but are difficult to establish via patient history. Please refer to UpToDate content on "COP
and evaluation" for additional information.
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Δ CAT: http://www.catestonline.org (Accessed on January 12, 2023).

◊ For those prescribed a LABA alone, SAMA-SABA combination therapy is likely to be most potent but wil
LAMA. For those prescribed a LAMA, SAMA should generally not be used concomitantly, so SABA alone is

§ Occasional patients with only minimal intermittent symptoms are appropriate for only as-needed rescu
acting bronchodilators.

Graphic 54300 Version 13.0

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Follow-up management of COPD*

No exacerbations and no dyspnea/low COPD impact (ie, mMRC 0 to 1 or CAT <10) ¶

Current therapy Actions

SABA or SABA-SAMA as Continue current therapy

needed

LAMA, LABA, or LAMA-LABA Continue current therapy

LABA-ICS or LABA-LAMA-ICS Taper or discontinue ICS dose to reduce adverse effects of

ICS Δ

Persistent dyspnea or high COPD impact (ie, mMRC ≥2 or CAT ≥10) ¶ with no
exacerbations

Current therapy Actions

SABA or SABA-SAMA as Add LAMA or LABA

needed

LAMA or LABA monotherapy Change to LAMA-LABA

LABA-ICS LAMA-LABA-ICS
LAMA-LABA if lack of response to ICS or adverse effects
from ICS

LAMA-LABA Substitute alternate delivery system or different LAMA-

LABA agents
Trial of LAMA-LABA-ICS, in patients with blood
eosinophils ≥100 cells/microL ◊
Additional interventions may include low-dose
theophylline, repeat pulmonary rehabilitation, and
nonpharmacologic therapies §

LAMA-LABA-ICS Continue LAMA-LABA-ICS

Additional interventions may include low-dose
theophylline, repeat pulmonary rehabilitation, and
nonpharmacologic therapies for COPD §
Stop ICS, if initial indication unclear, lack of response, or
adverse effect to ICS Δ

1 or more exacerbations in past year +/– persistent dyspnea or high COPD impact
(ie, mMRC ≥2 or CAT ≥10) ¶

Current therapy § Actions

SABA or SABA-SAMA as Add LAMA

needed

LAMA or LABA monotherapy LAMA-LABA, if blood eosinophil count <300/microL ◊

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or

LAMA-LABA-ICS, if blood eosinophil count ≥300/microL ◊

or hospitalization for COPD exacerbation

or

LABA-ICS, if blood eosinophil count ≥100/microL ◊ and

LAMA contraindicated

LAMA-LABA LAMA-LABA-ICS, if blood eosinophil count ≥100/microL ◊

or

Continue LAMA-LABA, if blood eosinophil count

<100/microL ¥
Add roflumilast ‡

or

Add azithromycin †

LABA-ICS LAMA-LABA-ICS

or

LAMA-LABA if lack of response to ICS or adverse effects

from ICS Δ

LAMA-LABA-ICS Continue LAMA-LABA-ICS

Add roflumilast ‡

or

Add azithromycin †
Stop ICS if initial indication unclear, lack of response, or
adverse effects of ICS Δ

COPD: chronic obstructive pulmonary disease; mMRC: modified Medical Research Council; CAT:
COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic-
antagonist; LAMA: long-acting muscarinic-antagonist; LABA: long-acting beta-agonist; ICS:
inhaled corticosteroids (glucocorticoids); BMI: body mass index; SpO2: pulse oxygen saturation;
FEV1: forced expiratory volume in one second.

* Adjustments to pharmacologic therapy for COPD are based on an assessment of

dyspnea/exercise limitation (mMRC or CAT), frequency of exacerbations, and peripheral blood
eosinophil counts. Follow-up visits are also an opportunity to assess and reinforce
nonpharmacologic interventions for COPD, including: smoking cessation; inhaler technique and
adherence to medications; administration of pneumococcal and seasonal influenza vaccinations;
pulmonary rehabilitation; and nutrition counselling regarding healthy diet and normal BMI. All
patients with COPD should have a rapid relief inhaler available, either a SABA or a SABA-SAMA
(SABA preferred for patients using a LAMA). Refer to UpToDate content on the overview of
management for stable COPD.

¶ mMRC dyspnea scale: https://www.pcrs-uk.org/mrc-dyspnoea-scale; CAT evaluates health

impact of COPD: https://www.catestonline.org.

Δ If blood eosinophil count ≥300 cells/microL, patient is more likely to experience exacerbations
after ICS withdrawal Close patient monitoring is required if ICS are withdrawn
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after ICS withdrawal. Close patient monitoring is required if ICS are withdrawn.

◊ In patients with exacerbations and blood eosinophil count ≥300 cells/microL, the addition of
ICS is likely to be of benefit. For patients with eosinophil counts ≥100 but <300 cells/microL, ICS
may improve exacerbation rates and pulmonary function.

§ Nonpharmacologic measures (eg, oxygen therapy if SpO2 ≤88%, pulmonary rehabilitation,

bronchoscopic or surgical lung volume reduction, lung transplantation) can help reduce dyspnea
and exacerbations. Contributing comorbidities should be evaluated and treated. Not all patients
achieve control of dyspnea or exacerbations despite optimal available pharmacotherapy.

¥ For patients with a blood eosinophil count <100 cells/microL, there is a low likelihood that
addition of ICS will be beneficial and higher risk of pneumonia after the addition of ICS.

‡ Roflumilast is used for patients with chronic bronchitis and FEV1 <50% predicted, particularly if
there has been at least 1 hospitalization for an exacerbation in the past year. Potential adverse
effects may limit use.

† A terapia preventiva com azitromicina é mais eficaz em pacientes que não são fumantes atuais.
No entanto, pode levar ao desenvolvimento de organismos resistentes.

Adaptado de: Iniciativa Global para Doença Pulmonar Obstrutiva Crônica (GOLD). Estratégia Global para o Diagnóstico,
Gestão e Prevenção da Doença Pulmonar Obstrutiva Crónica (Relatório de 2023). Disponível em: www.goldcopd.org
(Acessado em 13 de dezembro de 2022).

Gráfico 122795 Versão 4.0

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Contributor Disclosures
James K Stoller, MD, MS Grant/Research/Clinical Trial Support: Alpha-1 Foundation [Alpha-1
antitrypsin detection]. Consultant/Advisory Boards: 23andMe [Alpha-1 antitrypsin deficiency]; 4DMT
[Alpha-1 antitrypsin deficiency]; Alpha-1 Foundation [Member, Board of Directors]; Bridgebio [Alpha-1
antitrypsin deficiency]; CSL Behring [Alpha-1 antitrypsin detection]; Dicerna [Alpha-1 antitrypsin
deficiency]; Grifols [Alpha-1 antitrypsin detection]; InhibRx [Alpha-1 antitrypsin deficiency]; Insmed
[Alpha-1 antitrypsin deficiency]; Korro [Alpha-1 antitrypsin deficiency]; Takeda [Alpha-1 antitrypsin
detection]; Vertex [Alpha-1 antitrypsin deficiency]. All of the relevant financial relationships listed have
been mitigated. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca
[Asthma, COPD]; Boehringer [COPD]; Novartis [COPD]. Consultant/Advisory Boards: AstraZeneca
[Asthma, COPD]; Boehringer [COPD]; Epi-Endo [Asthma, COPD]; Novartis [COPD]; Teva [COPD].
Speaker's Bureau: AstraZeneca [Asthma]; Boehringer [COPD]; Novartis [COPD]; Teva [Asthma]. All of the
relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial
relationship(s) with ineligible companies to disclose.

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