Pulmonol.

2018;24(6):345---350

www.journalpulmonology.org

REVIEW

COPD exacerbations: management and hospital

discharge
A.J. Reis a , C. Alves b , S. Furtado c , J. Ferreira d , M. Drummond e,f , C. Robalo-Cordeiro g,h,∗ ,
on behalf of the GI DPOC-Grupo de Interesse na Doença Pulmonar Obstrutiva Crónica

a
Pulmonology Department, Hospital São Teotónio, Viseu, Portugal
b
Pulmonology Department, Hospital de Nossa Senhora do Rosário, Barreiro, Portugal
c
Pulmonology Department, Hospital Beatriz Ângelo, Loures, Portugal
d
Pulmonology Department, Unidade Local de Saúde de Matosinhos, Portugal
e
Pulmonology Department, Centro Hospitalar de São João, Porto, Portugal
f
Porto Medical School, Porto University, Portugal
g
Pulmonology Department, University Hospital, Coimbra, Portugal
h
Coimbra Medical School, Coimbra University, Portugal

Received 18 May 2018; accepted 17 June 2018

KEYWORDS Abstract Chronic Obstructive Pulmonary Disease (COPD) is a serious pulmonary condition.
COPD; Many patients experience exacerbations and some require Emergency Room visits and hospi-
Exacerbation; talization. In Portugal, hospitalizations due to COPD between 2009 and 2016 decreased by 8%,
Hospitalization; but they still represented 8049 hospitalized patients in 2016. Appropriate management of COPD
Management; exacerbations presents a clinical challenge and, in order to guide therapy, it is important to
Discharge identify the underlying cause; however, this is not possible in about a third of severe COPD
exacerbations. There are several diagnostic tools that can be used to assess an exacerbation
and its severity, which will in turn guide treatment, and prognostic scores should be used to
predict the risk of future exacerbations. After an exacerbation is appropriately managed, a
suitable discharge plan should be prepared. This should generally include reclassification of
the patient according to GOLD criteria, optimization of pharmacological therapy, management
of comorbidities, patient (or caregiver) education on the correct use of medications, refer-
ral to a Pulmonology Outpatient Clinic, if they are not already attending one, and a smoking
cessation and respiratory rehabilitation program. In this paper, we will focus on the pharmaco-
logical strategies for the management of COPD exacerbations, risk stratification and a hospital
discharge plan proposal.
© 2018 Published by Elsevier España, S.L.U. on behalf of Sociedade Portuguesa de Pneumologia.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

∗ Corresponding author at: Pulmonology Department, University

Hospital, 3000 Coimbra, Portugal.

E-mail address: [email protected] (C. Robalo-Cordeiro).

https://doi.org/10.1016/j.pulmoe.2018.06.006
2531-0437/© 2018 Published by Elsevier España, S.L.U. on behalf of Sociedade Portuguesa de Pneumologia. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
346 A.J. Reis et al.

Introduction infection,4 either viral4,9,14,15 or bacterial,4,9,15 but in about

a-third of severe exacerbations of COPD a cause cannot be
Chronic Obstructive Pulmonary Disease (COPD) is a seri- identified.1
ous pulmonary condition, which is slowly progressive with It is important to identify the underlying cause of an
systemic repercussions; it mainly affects people over 40 exacerbation as this will guide the therapeutic strategy.
years old.1 However, COPD is preventable and treatable.
Many patients experience COPD exacerbations and some of Classification
these require Emergency Room (ER) visits and hospitaliza-
tions. In Portugal, and although hospitalizations due to COPD As with the lack of definition of an exacerbation, there is
between 2009 and 2016 have decreased by 8%, they still rep- no consensual classification system to assess the exacerba-
resented 8049 hospitalized patients in 2016. Hospitalizations tion severity, although some have been proposed.16 Some of
of patients aged 80 years or more increased from 28.4% in these scores will be discussed further.
2005 to 38.0% in 2014, reflecting an aging population,2 with In mild exacerbations there is a worsening of symptoms
potentially more comorbidities. which can be managed at home, with an increase in dosage
Appropriate management of COPD exacerbations repre- of regular medications.1,6,17 Moderate exacerbations do not
sents an important clinical challenge.3 In 70% to 80% of COPD respond to an increased dosage of bronchodilators and
exacerbations, the precipitant factor is a respiratory tract therefore require treatment with systemic corticosteroids
infection,4 but in about a third of severe exacerbations of and/or antibiotics.1,6,17,18 Severe exacerbations require hos-
COPD a cause cannot be identified,1 which hampers proper pitalization or evaluation in the ER1,6,17,18 and have a
guidance of the therapeutic strategy. There are several diag- severe impact on physical activity. Very severe exacerba-
nostic tools to assess an exacerbation and its severity, which tions require admission to an Intensive Care Unit (ICU)1 and
will help in decisions like whether patient can be managed have a very severe impact on physical activity. Infectious
at home or in a primary care setting or if he/she should exacerbations are characterized by increases in volume and
be referred to an ER and eventually hospitalized.1,5---7 The purulence of the sputum associated with aggravated dys-
severity of an exacerbation will inform its treatment,1,7,8 pnea and should be treated with antibiotics.1,8
and prognostic scores should be used to predict the risk of
a future exacerbation. Three prognostic scores have been
proposed based on biological and clinical characteristics of Diagnostic tools
exacerbations: the BAP-65 score,9 the DeCOPD score9 and
the score proposed by Roche et al.10,11 The assessment of an exacerbation and its severity is based
After an exacerbation is appropriately managed, a suit- on the patient’s medical history,1,6 e.g., airflow limitation,
able discharge plan should be prepared. This will depend duration of worsening of symptoms and number of pre-
on the severity of the exacerbation, but should gen- vious episodes (total/hospitalizations). Symptoms such as
erally include reclassification of the patient according breathlessness, cough or sputum,7 oxygen saturation levels,7
to the GOLD criteria,1 optimization of pharmacological new limitation of daily activities,6,7 clinical signs of severity
therapy,1,4,8 management of comorbidities, patient (or home such as use of accessory respiratory muscles,1,5 paradoxical
caregiver) education on the correct use of medications,1,8 chest wall movements,1,5 worsening or new onset central
referral to a Pulmonology Consultation if they are not cyanosis,1,7 development of peripheral edema,1,7 hemo-
already attending one, and a smoking cessation and pul- dynamic instability,1 deteriorated mental status1,6,7 and
monary rehabilitation program. comorbidities1 should all be assessed. Pulse oximetry should
be performed on all patients.6 If a patient is referred to a
hospital, arterial blood gases should be measured5,6,8,15,19---21
Exacerbations and a chest radiography should be done to exclude comor-
bidities and/or other pulmonary diseases.1,6,8,15,19 In these
Definition, causes and etiology cases, it is also recommended that patients should have
an ECG,1,6,19,20 whole blood count,1,6,8,20---22 and basic bio-
Definition chemical tests, including electrolyte concentrations,1,8,20,21
Currently, there is no exact or consistent definition of a COPD urea,8 glycemia1,20 and metabolic panel.6 Theophylline lev-
exacerbation. The definition of exacerbation in the 2016 els should be measured in patients on theophylline therapy
GOLD update,12 ‘‘an acute event characterized by a wors- at admission and blood cultures should be taken if the
ening of the patient’s respiratory symptoms that is beyond patient has fever.8 Culture of sputum samples is not recom-
normal day-to-day variations and leads to a change in med- mended in routine practice, only if sputum is purulent,8 and
ication’’, was simplified in the GOLD 2017 document13 to the GOLD 2018 document recommends sputum culture and
‘‘an acute worsening of respiratory symptoms that results an antibiotic sensitivity test only if an infectious exacerba-
in additional therapy’’. tion does not respond to the empirical antibiotic treatment.1
Some authors mention eosinophilia blood count as an advis-
able procedure to guide COPD exacerbations therapy since
Causes and etiology it has been suggested that eosinophilic exacerbations may
be more responsive to systemic steroids.1,15 Spirometry is
Several factors that can lead to a worsening of symptoms not recommended during an exacerbation.1
have been identified, and in 70% to 80% of COPD exacer- If the exacerbation is severe and the patient hos-
bation cases, the precipitant factor is a respiratory tract pitalized, brain natriuretic peptide and cardiac enzyme
COPD exacerbations: management and hospital discharge 347

measurements levels should be considered, especially if infection.1,4,6---8,31 Antibiotics should only be used for the
the patient is not responding to conventional treatment.6 treatment of infectious4,6,8,31 or severe exacerbations.31 The
Also, pharyngeal swab or sputum should be tested for GOLD 2018 and NHS 2014 documents recommend antibi-
viruses and bacteria14,20,23 and serum C-reactive protein otics for patients with COPD exacerbations who have three
measured.14,20,24 Procalcitonin may guide antibiotic ther- cardinal symptoms --- increase in dyspnea, sputum vol-
apy since it has been suggested as a more specific marker ume, and sputum purulence7 (Evidence B)1 ; have two of
for bacterial infections and that may be of value in the cardinal symptoms, if increased purulence of spu-
deciding on antibiotics prescription.1 The Charlson comor- tum is one of the two symptoms7 (Evidence C)1 ; or
bidity index,5,20,21,23 the modified Medical Research Council require mechanical ventilation (invasive or non-invasive)
(mMRC) dyspnea scale,5,20,21,23 physical activity5 and general (Evidence B).1
health5 should be assessed. The authors do not advise the Antibiotics have been shown to reduce the risk of short-
use of COPD Assessment Test (CAT) score23 routinely in Por- term mortality, treatment failure and sputum purulence,
tugal as it is not validated for the Portuguese population. If and a study in COPD patients with exacerbations requiring
the patient is admitted to the ICU, besides the tests recom- mechanical ventilation (invasive or non-invasive) indicated
mended in severe exacerbations, the Glasgow Coma Scale5 that not treating with antibiotics was associated with
should be used, respiratory tract infections investigated25 increased mortality and a greater incidence of secondary
and a hemoculture performed.24 According to the GOLD 2018 nosocomial pneumonia.1 A Cochrane review concluded that
document only patients requiring non-invasive ventilation antibiotics for very severe COPD exacerbations showed wide
(NIV) or invasive ventilation (IV) should be hospitalized.1 and consistent beneficial effects across outcomes of patients
admitted to an ICU,32 but this conclusion was based on data
Pharmacologic strategies from a single study.32
The NHS protocol for management of COPD exa-
LABA + LAMA cerbations in primary care states that bronchodilators
and corticosteroids are the mainstay of exacerbation
Short-acting inhaled ␤2 agonists (SABAs) and short-acting treatment.7 However, a systematic review of 19 COPD
muscarinic antagonists (SAMAs) remain the mainstay in the guidelines reported that the criteria for treating patients
treatment of symptoms and airflow obstruction during COPD with antibiotics were largely based on an increase in
exacerbations.1,4,6 Although at the time of publication of the respiratory symptoms, while systemic corticosteroids were
GOLD 2018 document there were no clinical studies eval- often universally recommended for all patients with acute
uating the usefulness of long-acting ␤2 agonists (LABA) or exacerbations.33 The authors also concluded that current
long-acting muscarinic antagonists (LAMA) in exacerbations, COPD guidelines are of little help in identifying patients
the recommendation is to continue this medication during with acute exacerbations who are likely to benefit from
the exacerbation or to start it as soon as possible before hos- treatment with systemic corticosteroids and antibiotics in
pital discharge.1 The LABA + LAMA combination does have primary care, which might contribute to overuse or inap-
a documented benefit in the reduction of exacerbations propriate use of either treatment.
when prescribed to patients in the stable phase of COPD,26 Some biomarkers have been suggested as useful for opti-
particularly the indacaterol/glycopyrronium combination as mizing antibiotic treatment. The GOLD 2018 document1 does
demonstrated in the SPARK27 and FLAME28 studies. More- not recommend that CRP be used routinely but state that
over, the recent FLAME study,28 the first prospective study several studies have suggested that procalcitonin-guided
evaluating blood eosinophilia as a biomarker of therapeutic antibiotic treatment reduces antibiotic exposure and side
response, showed that indacaterol/glycopyrronium demon- effects with the same clinical efficacy. This observation
strated a significant improvement in lung function compared is corroborated by a Cochrane review demonstrating that
with salmeterol/fluticasone for all the cutoffs analyzed.29 A procalcitonin can guide antibiotic therapy.32 In contrast,
recent post hoc analysis of the WISDOM study identified a other authors reported that CRP might be a more valu-
subgroup of patients --- patients with ≥2 exacerbations and able marker,34 and a real-life primary care study concluded
≥400 cells/␮L --- that seem to be at increased risk of exacer- that performing CRP rapid tests led general practition-
bation when discontinued from ICS.30 In fact, and according ers to prescribe fewer antibiotics than those who did
to the most recent version of the GOLD document,1 symp- not.35
tomatic patients in the stable phase of COPD and a history For all patients, the choice of antibiotic should be guided
of ≥2 moderate exacerbations, or 1 with hospital admis- by the local bacterial resistance pattern,1,8 the microbiology
sion, in the past year, may benefit from an ICS on top of story of the patient and his/her risk factors.
LABA/LAMA. However, it is yet to be established whether Usually initial empirical treatment encompasses
blood eosinophils can be used as a biomarker to predict ICS aminopenicillin with clavulanic acid, a macrolide, or a
efficacy in terms of exacerbation prevention, as suggested tetracycline.1,8 However, the long-term use of macrolides
by the WISDOM post hoc analysis.1 may be associated with important side-effects and the
risk of developing bacterial resistance.36 Sputum should
Antibiotics, corticosteroids and xanthines be sent for culture (in the case of patients with frequent
When treating an exacerbation adding oral or intra- exacerbations, severe airflow limitation, and/or exacerba-
venous corticosteroids and/or antibiotics is recommended, tions requiring mechanical ventilation1 ), as gram-negative
depending on symptom severity and the presence of bacteria (e.g., Pseudomonas species) or resistant pathogens
348 A.J. Reis et al.

that are not sensitive to the above-mentioned antibiotics given an oral corticosteroid6,17,18 for 5 days.1,38,39 If the exac-
may be present.1 erbation is infectious4,8,31 an antibiotic should be given.1,7
Although the most effective duration of treatment is still In the case of a patient who has had a severe exac-
to be defined,32 the recommended length of antibiotic ther- erbation, requiring hospitalization, the patient should be
apy is usually 5---7 days (Evidence D)1 but treatment duration reclassified as a frequent exacerbator. Usually, hospitaliza-
will depend on the antibiotic used. tion due to a severe exacerbation requires modification of
The management of exacerbations in primary care inhaled maintenance treatment including O2 if the patient is
should include maximization of bronchodilator therapy and hypoxemic and non-invasive ventilation if patient has hyper-
systemic corticosteroids if not contraindicated (30 mg pred- capnia, greater than 52 cm H2 O and/or acidemia,1,4,6,8 oral
nisolone) for 7 days.1,7,8 Therapy with oral prednisolone or intravenous corticosteroids (for 5 days)1,38,39 and antibi-
is equally as effective as intravenous administration.1 The otic if infectious,1,7 xanthines if there is an inadequate
GOLD 2018 document recommends a dose of 40 mg pred- response to treatment4,8,16,31 and prevention of pulmonary
nisone per day for 5 days1 whilst NICE 2016 recommends a thromboembolism.
dose of 30 mg for 7---14 days, and further recommends that
a course of corticosteroid treatment should not be longer
than 14 days as there is no advantage in prolonged therapy.8 Discharge --- action plan
The use of systemic corticosteroids in COPD exacerbations
have been shown to shorten recovery time, improve lung Patients with mild exacerbations should be re-assessed after
function, improve oxygenation, decrease the risk of early three months, with spirometry and a re-evaluation of the
relapse and treatment failure, and decrease the length of GOLD degree and, when appropriate, reclassification.
hospitalization.1 On discharge from a moderate exacerbation, bronchodi-
A meta-analysis confirmed that the rate of treatment lation should be optimized, anti-pneumococcal vaccination
success increased with systemic corticosteroids in compar- should be prescribed, and a smoking cessation and respira-
ison to usual care of COPD exacerbations. Corticosteroids tory rehabilitation plan should be prepared.
seem to be beneficial to the whole population in terms of On discharge after a severe exacerbation, optimal main-
treatment success rate.37 tenance therapy1,4,8 with LABA, LAMA and ICS should be
Some studies suggest that corticosteroids may be less prescribed. Patients who have had an episode of respira-
efficacious in treating acute COPD exacerbations in patients tory failure should have satisfactory oximetry or arterial
with lower levels of blood eosinophils.15,38 blood gas results before discharge. Patients (or home care-
As for methylxanthines in the management of COPD exa- givers) should be given appropriate information to enable
cerbations, current evidence does not support their use, them to fully understand the correct use of medications,
given that the possible beneficial effects in lung function including inhalers and oxygen, and, if necessary, arrange-
and clinical endpoints are modest and inconsistent, whilst ments for follow-up and home care (such as visiting nurse,
adverse events are significant.1,4,6,31 Intravenous methylx- oxygen delivery, referral for other support) should be made.
anthines (theophylline or aminophylline) may be considered The patient, patient’s caregiver and the physician should
second-line therapy and used as an add-on when there is be confident that he or she can successfully manage the
insufficient response. When using theophylline, it is neces- new treatment plan. When there is any doubt about the
sary to monitor blood levels, side effects and potential drug patient’s capacity to manage his/her therapy, a formal activ-
interactions.8,31 ities of daily living assessment may be helpful.8 The GOLD
2018 document provides a list of discharge criteria.1 For
patients who are hypoxemic during an exacerbation, arte-
rial blood gases and/or pulse oximetry should be evaluated
Therapeutics --- risk stratification prior to hospital discharge and in the following 3 months.
Exacerbations of COPD may be classified as mild, moderate, If the patient remains hypoxemic, long-term supplemental
severe6 and very severe. Very severe exacerbations require oxygen therapy may be required.1 Also, patients should be
admission to the ICU, with invasive ventilation, and are out- given clear instructions about when and how to stop their
side the scope of this paper. corticosteroid treatment.1,8 Concerning the need for indi-
As previously mentioned, exacerbations of COPD are very vidualized care, a Canadian study in which the patients were
heterogeneous making it particularly relevant to determine offered a post discharge phone call, a home visit and con-
their etiology, pathology, severity and risk as all of these fac- tinued care concluded that although there was no reduction
tors will have implications in the prognosis, pharmacological in 30- and 90-day readmission rates, a decrease in 90-day
treatment and place of treatment. total mortality was seen. These data suggest that the indi-
In terms of pharmacological treatment and place of treat- vidualized care undertaken in this study can impact COPD
ment, if exacerbations are mild and non-infectious,1,4,7,8,31 morbidity and mortality after an acute exacerbation.40 All
they may be treated at home with an increase in the dosage patients who have had a severe exacerbation should be re-
of maintenance bronchodilators.6,17 If the exacerbation is assessed 4---6 weeks after discharge from hospital,1 given
infectious4,8,31 an antibiotic should be given.1,7 an anti-pneumococcal vaccination prescription, and a smok-
Moderate exacerbations should be treated in the ER and ing cessation and respiratory rehabilitation plan should be
the patient then discharged as these exacerbations do not prepared --- Fig. 1.
require hospitalization, unless the hospitalization occurs for The authors propose that the patient should be pre-
socioeconomic reasons. The dosage of maintenance bron- scribed an anti-pneumoccocal vaccine 10 to 20 days after
chodilators should be increased6,17 and the patient been discharge from the ER or Hospital.
COPD exacerbations: management and hospital discharge 349

MILD MODERATE SEVERE VERY SEVERE

exacerbation exacerbation exacerbation exacerbation

Optimization of inhaled • Optimization of inhaled • Oral corticosteroid ICU

bronchodilators bronchodilators
• Antibiotic if patient has three
• Oral corticosteroid cardinal symptoms - increase
in dyspnea, sputum volume,
• Antibiotic if increase in sputum
Discharge and sputum purulence; two
volume, and sputum purulence
of the cardinal symptoms,
if increase purulence of
sputum is one of the two;
Discharge or if mechanical ventilation
(invasive or noninvasive) is
required
• Xanthines if inadequate
• Re-assess up to 90 days response to treatment

• Anti-pneumococcal vaccination • Prevention of pulmonary

thromboembolism
• Smoking cessation*
• Hospitalization with O2 if
• Respiratory rehabilitation** hypoxemic and non-invasive
ventilation if hypercapnia

Discharge

• Re-assess up to 30 days
• Anti-pneumococcal vaccination
• Smoking cessation*
* If aplicable. ** If not yet in the treatment plan. • Respiratory rehabilitation**

Fig. 1 Proposed therapy, discharge and follow-up of mild, moderate, severe and very severe COPD exacerbations.

During the follow-up consultation (three months for fees from AstraZeneca, Boehringer Ingelheim, Diater,
moderate exacerbations and 4---6 weeks for severe exa- Inmunotek, Menarini, Mundipharma, Mylan, Tecnifar and
cerbations), spirometry and arterial blood gases should TEVA, and participating in advisory boards of Bial, GSK and
be measured. Symptoms, correct use of inhaled therapy Novartis. MD declares having received fees for talks from
and adequate management of comorbidities should be re- AstraZeneca, Boehringher Ingelheim, Bial, GSK, Menarini
assessed. Pharmacological treatment should be optimized. and Novartis and for participation in advisory boards of
The smoking cessation and respiratory rehabilitation plan Bial, GSK and Novartis. CRC declares speaking fees from
should be evaluated. A new follow-up consultation should Boehringer Ingelheim, Roche, Novartis, AstraZeneca, Pfizer
be scheduled within the next 30---60 days. vaccines, Teva, Menarini, Medinfar and Tecnifar, and partic-
ipating in advisory boards of Boehringer Ingelheim, Roche,
Novartis, GSK, AstraZeneca and Pfizer vaccines.
Conclusions

Identification of the underlying cause of COPD exacerba- Acknowledgements

tions and assessment of their severity is fundamental to
guiding treatment. After an exacerbation is appropriately Funding for this paper was provided by Novartis Portugal.
managed, a suitable discharge plan that will depend on its Funding was used to access all necessary scientific bibliog-
severity should be prepared. A proper discharge plan will raphy and cover meeting expenses. Novartis Portugal had no
decrease symptom burden, contribute to a faster recovery, role in the collection, analysis and interpretation of data, in
increase the patient’s quality of life, and prevent or delay the writing of the paper and in the decision to submit the
future exacerbations. Referral to a Pulmonology Consulta- paper for publication.
tion if the patient is not already attending one is of the
utmost importance.
References
Conflicts of interest
1. Global Initiative for Chronic Obstructive Lung Disease. Global
strategy for the diagnosis, management and prevention of
AR declares having received speaking fees from chronic obstructive pulmonary disease; 2018.
AstraZeneca, Boehringer Ingelheim, Novartis, Bial, Med- 2. Portugal I. A evolução da Doença Pulmonar Obstrutiva Crónica
infar, Mundipharma, Menarini, Grifols, Mylan, Tecnifar, no internamento hospitalar entre 2005---2014; 2015.
Teva and cslbehring. CA declares having received speaking 3. Miravitlles M, D’Urzo A, Singh D, Koblizek V. Pharmacological
fees from AstraZeneca, Pfizer, Novartis and Mundipharma. strategies to reduce exacerbation risk in COPD: a narrative
SF declares no conflicts of interest. JF declares speaking review. Respir Res. 2016;17:112.
350 A.J. Reis et al.

4. Qureshi H, Sharafkhaneh A, Hanania NA. Chronic obstructive 24. Salturk C, Karakurt Z, Adiguzel N, Kargin F, Sari R, Celik ME,
pulmonary disease exacerbations: latest evidence and clinical et al. Does eosinophilic COPD exacerbation have a better
implications. Ther Adv Chronic Dis. 2014;5:212---27. patient outcome than non-eosinophilic in the intensive care
5. Esteban C, Arostegui I, Garcia-Gutierrez S, Gonzalez N, unit? Int J Chron Obstruct Pulmon Dis. 2015;10:1837---46.
Lafuente I, Bare M, et al. A decision tree to assess short-term 25. Planquette B, Peron J, Dubuisson E, Roujansky A, Laurent V, Le
mortality after an emergency department visit for an exacer- Monnier A, et al. Antibiotics against Pseudomonas aeruginosa
bation of COPD: a cohort study. Respir Res. 2015;16:151. for COPD exacerbation in ICU: a 10-year retrospective study.
6. Evensen AE. Management of COPD exacerbations. Am Fam Phys. Int J Chron Obstruct Pulmon Dis. 2015;10:379---88.
2010;81:607---13. 26. Cohen JS, Miles MC, Donohue JF, Ohar JA. Dual therapy strate-
7. NHS. Protocol for management of COPD exacerbation in primary gies for COPD: the scientific rationale for LAMA + LABA. Int J
care; 2014. Chron Obstruct Pulmon Dis. 2016;11:785---97.
8. NICE. Managing exacerbations of COPD; 2016. 27. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sand-
9. Lopez-Campos JL, Agusti A. Heterogeneity of chronic obstruc- strom T, Taylor AF, et al. Analysis of chronic obstructive
tive pulmonary disease exacerbations: a two-axes classification pulmonary disease exacerbations with the dual bronchodilator
proposal. Lancet Respir Med. 2015;3:729---34. QVA149 compared with glycopyrronium and tiotropium (SPARK):
10. Roche N, Zureik M, Soussan D, Neukirch F, Perrotin D. Predic- a randomised, double-blind, parallel-group study. Lancet Respir
tors of outcomes in COPD exacerbation cases presenting to the Med. 2013;1:199---209.
emergency department. Eur Respir J. 2008;32:953---61. 28. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N,
11. Roche N, Chavaillon JM, Maurer C, Zureik M, Piquet J. A clinical Ayers RT, et al. Indacaterol-glycopyrronium versus salmeterol-
in-hospital prognostic score for acute exacerbations of COPD. fluticasone for COPD. N Engl J Med. 2016;374:2222---34.
Respir Res. 2014;15:99. 29. Roche N, Chapman KR, Vogelmeier CF, Herth FJ, Thach C, Fogel
12. Global Initiative for Chronic Obstructive Lung Disease. Global R, et al. Blood eosinophils and response to maintenance COPD
strategy for the diagnosis, management and prevention of treatment: data from the FLAME trial. Am J Respir Crit Care
chronic obstructive pulmonary disease (updated 2016); 2016. Med. 2017.
13. Global Initiative for Chronic Obstructive Lung Disease. Global 30. Calverley PM, Tetzlaff K, Vogelmeier C, Fabbri LM, Magnussen
strategy for the diagnosis, management and prevention of H, Wouters EF, et al. Eosinophilia, frequent exacerbations, and
chronic obstructive pulmonary disease (2017 report); 2017. steroid response in chronic obstructive pulmonary disease. Am
14. Clark TW, Medina MJ, Batham S, Curran MD, Parmar S, Nicholson J Respir Crit Care Med. 2017.
KG. C-reactive protein level and microbial aetiology in patients 31. Ferreira J, Drummond M, Pires N, Reis G, Alves C, Robalo-
hospitalised with acute exacerbation of COPD. Eur Respir J. Cordeiro C. Optimal treatment sequence in COPD: can a
2015;45:76---86. consensus be found? Rev Port Pneumol (2006). 2016;22:39---49.
15. Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, et al. 32. Vollenweider DJ, Jarrett H, Steurer-Stey CA, Garcia-Aymerich
Acute exacerbations of chronic obstructive pulmonary disease: J, Puhan MA. Antibiotics for exacerbations of chronic
identification of biologic clusters and their biomarkers. Am J obstructive pulmonary disease. Cochrane Database Syst Rev.
Respir Crit Care Med. 2011;184:662---71. 2012;12:CD010257.
16. Guimaraes M, Bugalho A, Oliveira AS, Moita J, Marques A. COPD 33. Laue J, Reierth E, Melbye H. When should acute exacerbations
control: can a consensus be found? Rev Port Pneumol (2006). of COPD be treated with systemic corticosteroids and antibiotics
2016;22:167---76. in primary care: a systematic review of current COPD guidelines.
17. Montserrat-Capdevila J, Godoy P, Marsal JR, Barbe F. Predic- NPJ Prim Care Respir Med. 2015;25:15002.
tive model of hospital admission for COPD exacerbation. Respir 34. Daniels JM, Schoorl M, Snijders D, Knol DL, Lutter R, Jansen HM,
Care. 2015;60:1288---94. et al. Procalcitonin vs C-reactive protein as predictive mark-
18. Criner GJ, Bourbeau J, Diekemper RL, Ouellette DR, Goodridge ers of response to antibiotic therapy in acute exacerbations of
D, Hernandez P, et al. Executive summary: prevention of acute COPD. Chest. 2010;138:1108---15.
exacerbation of COPD: American College of Chest Physicians and 35. Llor C, Bjerrum L, Munck A, Hansen MP, Cordoba GC, Strandberg
Canadian Thoracic Society Guideline. Chest. 2015;147:883---93. EL, et al. Predictors for antibiotic prescribing in patients with
19. Rivas-Ruiz F, Redondo M, Gonzalez N, Vidal S, Garcia S, Lafuente exacerbations of COPD in general practice. Ther Adv Respir Dis.
I, et al. Appropriateness of diagnostic effort in hospital emer- 2013;7:131---7.
gency room attention for episodes of COPD exacerbation. J Eval 36. Miravitlles M, Anzueto A. A new two-step algorithm for the
Clin Pract. 2015;21:848---54. treatment of COPD. Eur Respir J. 2017:49.
20. Guerrero M, Crisafulli E, Liapikou A, Huerta A, Gabarrus A, 37. Abroug F, Ouanes I, Abroug S, Dachraoui F, Abdallah SB, Ham-
Chetta A, et al. Readmission for acute exacerbation within 30 mouda Z, et al. Systemic corticosteroids in acute exacerbation
days of discharge is associated with a subsequent progressive of COPD: a meta-analysis of controlled studies with emphasis
increase in mortality risk in COPD patients: a long-term obser- on ICU patients. Ann Intensive Care. 2014;4:32.
vational study. PLOS ONE. 2016;11:e0150737. 38. Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge
21. Lun CT, Tsui MS, Cheng SL, Chan VL, Leung WS, Cheung AP, P, et al. Blood eosinophils to direct corticosteroid treatment
et al. Differences in baseline factors and survival between of exacerbations of chronic obstructive pulmonary disease: a
normocapnia, compensated respiratory acidosis and decompen- randomized placebo-controlled trial. Am J Respir Crit Care Med.
sated respiratory acidosis in COPD exacerbation: a pilot study. 2012;186:48---55.
Respirology. 2016;21:128---36. 39. Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher
22. Chang CH, Tsao KC, Hu HC, Huang CC, Kao KC, Chen NH, T, et al. Short-term vs conventional glucocorticoid therapy
et al. Procalcitonin and C-reactive protein cannot differenti- in acute exacerbations of chronic obstructive pulmonary dis-
ate bacterial or viral infection in COPD exacerbation requiring ease: the REDUCE randomized clinical trial. JAMA. 2013;309:
emergency department visits. Int J Chron Obstruct Pulmon Dis. 2223---31.
2015;10:767---74. 40. Adamson SL, Burns J, Camp PG, Sin DD, van Eeden SF. Impact of
23. Dai MY, Qiao JP, Xu YH, Fei GH. Respiratory infectious pheno- individualized care on readmissions after a hospitalization for
types in acute exacerbation of COPD: an aid to length of stay acute exacerbation of COPD. Int J Chron Obstruct Pulmon Dis.
and COPD Assessment Test. Int J Chron Obstruct Pulmon Dis. 2016;11:61---71.
2015;10:2257---63.