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The recent advances of phenotypes in acute

exacerbations of COPD
This article was published in the following Dove Press journal:
International Journal of COPD
27 March 2017
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Aiyuan Zhou 1–3 Abstract: Exacerbations of COPD are clinically relevant events with therapeutic and prognostic
Zijing Zhou 1–3 implications. Yet, significant heterogeneity of clinical presentation and disease progression exists
Yiyang Zhao 1–3 within acute exacerbations of COPD (AECOPD). Currently, different phenotypes have been
Ping Chen 1–3 widely used to describe the characteristics among patients with AECOPD. This has proved to
be significant in the treatment and prediction of the outcomes of the disease. In this review
1
Department of Respiratory Medicine,
The Second Xiangya Hospital, of published literature, the phenotypes of AECOPD were classified according to etiology,
2
Research Unit of Respiratory inflammatory biomarkers, clinical manifestation, comorbidity, the frequency of exacerbations,
Disease, 3Diagnosis and Treatment and so on. This review concentrates on advancements in the use of phenotypes of AECOPD.
Center of Respiratory Disease,
Central South University, Changsha, Keywords: COPD, acute exacerbation, phenotype, treatment, prognosis
Hunan, People’s Republic of China

Abbreviations
ACOS, asthma–COPD overlap syndrome; AECOPD, acute exacerbations of COPD;
BODE, body mass index, airflow obstruction, dyspnea, and exercise capacity; CAT,
COPD Assessment Test; CCQ, Clinical COPD Questionnaire; CRP, C-reactive pro-
tein; ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate
Endpoints; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in
1 second; GesEPOC, Spanish COPD guidelines; GOLD, Global Initiative for Chronic
Obstructive Lung Disease; 4-HNE, 4-human neutrophil elastase; ICS, inhaled corticos-
teroids; ICU, intensive care unit; IL-6, interleukin-6; MBL, mannose-binding lectin;
MMP-9, matrix metalloproteinase-9; mMRC, modified medical research council;
MPO, myeloperoxidase; NETT, National Emphysema Treatment Trial; PF4, platelet
factor 4; PCT, procalcitonin; SAA, serum amyloid protein A; SP-D, serum surfactant
protein-D; TNT, troponin-T; VEGF, vascular endothelial growth factor.

Introduction
AECOPD is an acute event characterized by a worsening of the patient’s respiratory
symptoms that is beyond normal day-to-day variation and leads to change in
medication.1 At first glance, this definition seems straightforward. However, it has
several caveats and unknowns that differ according to each patient’s pathobiological
heterogeneity and different clinical presentation and management needs.
Correspondence: Ping Chen COPD phenotype is defined as “a single or combination of disease attributes
Department of Respiratory Medicine, that describe differences between individuals with COPD as they relate to clini-
The Second Xiangya Hospital, Central
South University, 139 Renmin Middle
cally meaningful outcomes”. Therefore, the phenotype should be able to be used to
Road, Changsha, Hunan 410011, classify patients into subgroups with a prognostic value that allows determining the
People’s Republic of China
Tel +86 731 8529 5248
best treatment in order to achieve better clinical results.2 In this way, we can take on
Email [email protected] a more personalized treatment according to the severity of the airflow obstruction and

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Zhou et al Dovepress

conditioned by the clinical phenotype. Recent findings sug- COPD were excluded. Moreover, the abstracts of the articles
gest that exacerbations of COPD are heterogeneous events not published in English were excluded. Two independent
and that this heterogeneity might have clinically relevant authors (AZ and ZZ) reviewed the title and abstract against
therapeutic and prognostic effects.3 In a viewpoint published the inclusion criteria. Disagreements between reviewers were
in the journal The Lancet Respiratory Medicine,4 the authors resolved through the third reviewer by discussion.
proposed a two-axis classification of exacerbations of COPD
by considering the pathobiological and clinical heterogene- Etiology phenotypes
ity of exacerbations of COPD. They stratified patients into It is well known that AECOPD may be triggered by infection
four groups (E1–E4), each of which might need a different with bacteria or viruses or by noninfectious environmental
treatment strategy and have a different short-term risk, and (eg, temperature, pollution, allergens, and diet) or internal
hence the need for a different care setting. Unfortunately, (immune dysregulation) factors. The cause of approximately
phenotype in AECOPD is still in a stage of exploration. It has one-third of exacerbations cannot be identified.5–7 Patients
always been classified based on different etiologies, clinical with detectable respiratory pathogens have been shown to
manifestations, biomarkers, comorbidities, frequencies of exhibit a more marked impact on lung function and longer
exacerbation, and so on. In this review, we mainly focus on duration of hospitalization than patients with exacerbations
the phenotypes that have been proven to have a therapeutic of noninfectious etiology.8 With in-depth studies of micro-
or prognostic effect on patients with AECOPD. organisms, some research concludes that there are differ-
ences in the clinical manifestation, treatment, and prognosis
Methods between bacterial infections and viral infections. Sore throat,
Search strategy cough, dyspnea, and chills are more common in viral infec-
A review was performed to identify research articles or tions than in bacterial infections.9 Viral exacerbations are
meta-analysis from 1986 to 2016 that assessed the charac- associated with higher IL-6 levels,10 lower levels of CRP,11
teristics, including etiology, manifestation, inflammatory and longer duration of hospital stay (average 9  days).12
cells, comorbidity, and frequency of exacerbation, which are However, as for antiviral treatment, the current therapies
related to different therapies or prognosis of patients with for the virus-induced exacerbations are not very effective.12
AECOPD. This review was performed on September 5, 2016, The guideline about the lower respiratory tract infection
in PubMed. The search strategy is shown in Table 1. treatment published in 2011 by the European Respiratory
Society pointed out that AECOPD patients usually were not
Eligibility criteria for study selection recommended to have empiric antiviral treatment. However,
Studies including articles or meta-analysis that focused if in flu season, or at high risk of flu, patients with typical
on any one of the characteristics associated with different influenza symptoms (such as fever, muscle pain, muscle
therapies or prognosis of the patients with AECOPD were weakness, and respiratory infection symptoms), if onset
included. Patients must be subjects older than 40 years diag- is within 2  days, should have antiviral treatment as early
nosed with AECOPD. Articles were excluded if they did not as possible.13 In bacterial exacerbations, purulent sputum
show the different traits based on the phenotypes, subgroups, is the typical symptom, as is neutrophil inflammation in
or heterogeneity. Studies that tested empirically defined both blood and airway. Levels of CRP and PCT would be
phenotypes without an analytical justification of these pheno- higher than those in non-bacterial exacerbations.14 Cited
types and those that concentrated on the phenotypes in stable guidelines suggest that exacerbations of COPD with puru-
lence of sputum are the most important symptom, which
Table 1 Search strategy calls for the use of antibiotics.15,16 Altogether, knowing the
PubMed strategy characteristics of various etiologies may have important
Step Search terms therapeutic implications and provide evidence for local
#1 “Acute exacerbation of Chronic Obstructive surveillance of AECOPD pathogens and appropriate choice
Pulmonary Disease” [Mesh] of antimicrobials. This may give clinicians some indications
#2 “Exacerbation of COPD” [Mesh] to avoid abusing antibiotics to some extent.
#3 #1 OR #2
#4 Phenotype[Text Word] OR subgroups[Text Word]OR
heterogeneity[Text Word] OR different characteristic Inflammatory phenotypes
[Text Word] Patients with AECOPD also display heterogeneous inflam-
#5 #3 AND #4
mation. At present, the diagnosis of AECOPD mainly

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Dovepress A review of the phenotypes of AECOPD

depends on clinical symptoms. There is lack of quantitative FeNO level correlated well with the eosinophils, which is a
indicators. Inflammatory markers as a kind of quantitative good predictor for the response to corticosteroids.41,42 Antus
indicator are widely used in judging acute exacerbation et al43 pointed out that the optimum cutoff point for FENO
and assessing prognosis. Systemic inflammatory markers as a predictor for significant increase in FEV1 was 26.8 ppb
mainly include CRP,17–19 PCT,20,21 serum amyloid A,22 (sensitivity: 74% and specificity: 75%). In addition, induced
SP-D,23 fibrinogen,24 inflammation cell chemotactic factor,25 sputum analysis has beneficial effects on the treatment and
and so on. All the markers mentioned earlier will increase prognosis of patients with AECOPD. Patients can be divided
in AECOPD patients and decrease in recovery. As a result into different phenotypes according to the type of inflam-
of these investigations using biomarkers, the patients were matory cells. These inflammatory phenotypes are clinically
divided into different phenotypes. relevant due to potential differences in the response to
CRP is one of the most important biomarkers. A small therapeutic interventions. Gao et al44 recently identified the
study reported that a cutoff value of 19.65 mg/L has a sensi- following four subgroups: eosinophilic predominant, neu-
tivity of 78% and a specificity of 84% to identify the bacterial trophilic predominant, paucigranulocytic predominant, and
origin of exacerbations of COPD. In patients with AECOPD mixed granulocytic predominant. The eosinophilic phenotype
with mucoid sputum, an elevated CRP level of .15.21 mg/L (EO) is so named when sputum eosinophils are .2.5% of
indicates bacterial infection.18 However, a study published total cells, the neutrophilic phenotype (NE) is the subgroup
recently found that PCT and CRP cannot differentiate having neutrophils .61%, the paucigranulocytic phenotype
between bacterial and viral infections in the exacerbations (PA) has eosinophils #2.5% and neutrophils #61%, and the
of COPD requiring emergency department visits.26 Another mixed granulocytic phenotype (MC) has eosinophils .2.5%
study showed that CRP .100 mg/mL was associated with and neutrophils .61%. Different phenotypes have different
a near fourfold increased probability of adverse outcome.27 pathological and physiological characteristics. The results of
PCT is also a very important marker in AECOPD. PCT this study showed that the patients with mixed granulocytic
level .0.5 ng/mL is independently associated with bacte- or neutrophilic AECOPD had a higher BODE score, more
rial isolation in severe AECOPD.21,28 In addition, in patients sputum inflammatory cells, lower lung function, and longer
who required intubation and mechanical ventilation, PCT hospital stay, accompanied by higher concentrations of
levels are independently associated with increased risk for sputum MMP-9, IL-6, and CRP and serum SAA, IL-6, and
ICU mortality.21 Yet, a post hoc analysis of a randomized, CRP. Notably, 83% of patients with neutrophilic AECOPD
placebo-controlled trial that failed to show a positive effect displayed evidence of bacterial infection and many of
of antibiotics in COPD exacerbations suggested that patients them responded poorly to standard therapies. Patients with
with low PCT concentrations during a COPD exacerbation EO, especially when combined with asthma, have a better
might also benefit from antibiotic treatment.29 Above all, the response to corticosteroids than the rest of the other types.45
results from a meta-analysis suggest that PCT-guided treat- Similar results were later reported by Bafadhel et al.46
ment can safely reduce antibiotic overuse in patients with Therefore, the classification of inflammatory cells in sputum
AECOPD,30 but the cutoff of PCT to use antibiotics has no and the level of FeNO are of great importance in assessing
consensus; further studies are needed to evaluate the utility the prognosis of patients and guiding whether or not to
of PCT measurement.31 use corticosteroids. However, although the identification
Some biomarkers, such as fibrinogen,32,33 TNT,34 VEGF,35 of inflammatory phenotype is meaningful for AECOPD,
4-HNE,36 PF4,37 β-thromboglobulin,38 and copeptin,19 may the sensitivity, specificity, and multiindex application of
also reflect the severity of AECOPD and can be used as this method on the efficiency of the diagnosis remain to be
prognostic markers. However, there is no cut point enabling further studied.47
these markers to differentiate between patients with different
phenotypes. In the period of AECOPD, the airway inflam- Clinical manifestation of phenotypes
mation is more severe than that in stable COPD. The most As mentioned earlier, AECOPD is a heterogeneous disease
widely used biomarkers of airway inflammation are FeNO and this heterogeneity can also be reflected in the symptoms.
and induced sputum analysis. Currently, FeNO is regarded as In exacerbations, the most important symptoms are increased
the most promising indicator.39 Some studies have reported dyspnea, sputum volume, and sputum purulence. Nowadays,
that patients with high FeNO levels will have a good response the recognized criterion used to classify AECOPD according
to corticosteroids and greater improvement in FEV1.39,40 to symptoms is the Anthonisen standard.48 Anthonisen et al48
The reason for this result may be due to the fact that the divided exacerbations into three types. Type 1 exacerbations

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involve increased dyspnea, sputum volume, and sputum 20% and 40% of COPD patients can be carriers of a mixed
purulence, Type 2 involve any two of the latter symptoms, phenotype.55 This newly described phenotype is called as the
and Type 3 just involves one of those symptoms combined ACOS.58,59 Patients with a history of asthma are more likely
with cough, wheeze, or symptoms of an upper respiratory to have a good response to corticosteroids,55 and the FEV1
tract infection. In Type 1 exacerbations, patients had an decreased faster than that in patients who have no asthma.60
improved response to the antibiotic therapy and the CRP level Furthermore, in GOLD 2014, bronchiectasis has been added
in Type 1 was more elevated than in the other two types. It is to the comorbidities of COPD. Patients with the diagnosis
recommended that antibiotics are used as early as possible of COPD who share the comorbidity of bronchiectasis will
in Type 1 exacerbations.49 Moreover, Stockley et al50 found experience longer exacerbations. The pathogens in patients
that the presence of green (purulent) sputum indicates a clear with AECOPD and bronchiectasis are complex and will
subset of patients identified at presentation who are likely to usually need broad-spectrum antibiotics.61,62
benefit most from antibiotic therapy. In addition, before an COPD can no longer be considered as a disease, which
episode of exacerbation, the prodromes are different among only affects the lungs. Increasing evidence supports the
patients. Aaron et al51 divided the exacerbations of COPD presence of a systemic inflammatory component, which
into two distinct patterns, such as sudden and gradual onsets, is thought to provide the link between COPD and other
according to worsening respiratory symptoms from diary extrapulmonary comorbidities.63,64 These include cardio-
cards. Patients who experienced sudden onset exacerba- vascular disorders, skeletal muscle dysfunction, diabetes,
tions had greater mean daily symptom scores, greater peak osteoporosis, anxiety, and depression. 65–68 Similarly, a
symptom scores, earlier peak symptoms, and shorter median multicenter Spanish study identified four COPD exacerba-
recovery times back to baseline health status. Above all, tion types (subtypes A–D, classified on the basis of their
these prodromes are important in differentiating the triggers clinical severity and presence or absence of comorbidities).
of exacerbations. For instance, dyspnea, common colds, sore Patients with these different subtypes of the disease required
throat, and cough increase significantly during the prodromal different hospital setting needs (regular ward vs intensive
phase, indicating that the triggers are more likely to be viral. care unit): subtype A (n=934), neither high comorbidity nor
Colds are even associated with longer and more severe exac- severe exacerbation; subtype B (n=682), moderate comor-
erbations, and there is no doubt that a COPD patient who bidities; subtype C (n=562), severe comorbidities related to
develops a cold should be considered for early therapy.52 mortality; and subtype D (n=309), very severe exacerba-
It is well known that the severity of COPD is assessed tion significantly related to mortality and admission to an
not only by lung function, but CAT, mMRC questionnaires, intensive care unit. Subtype D experienced the highest rate
and CCQ also have great importance in assessing the of mortality, admission to an intensive care unit, and need
disease severity and estimating the risk of exacerbations. for noninvasive mechanical ventilation. This was closely
In GOLD 2013, CAT and mMRC were used for grading followed by subtype C, while subtypes A and B were primar-
and different grades corresponded to different treatments.53 ily related to other serious complications. Hospitalization
According to the clinical manifestation of the phenotype, rate was .50% for all the subtypes, although significantly
the clinician can therefore provide more purposeful and higher for subtypes C and D than for subtypes A and B.69
individualized treatment. These results could help to identify characteristics in order to
categorize AECOPD patients for more appropriate care. They
Comorbidity phenotypes could also help in assessing interventions and treatments in
AECOPD is often accompanied by comorbidities, which subgroups with poor evolution and outcomes.
include not only the pulmonary disease but also the extra-
pulmonary disease. Comorbidities during hospital admis- Frequent exacerbations phenotypes
sion are associated with increased length of stay, mortality, The frequency of AECOPD is variable among patients.
and poor outcomes in patients with AECOPD.54 In terms Recently, a “frequent exacerbator” phenotype has been postu-
of the pulmonary comorbidity, it is very common to see a lated and examined in clinical studies. The pathophysiology
great number of patients who suffer COPD accompanied by underlying the frequent exacerbations phenotype includes
asthma,55 pneumonia,56 and lung cancer.57 Patients having the increased airway and systemic inflammation, dynamic lung
characteristics that are attributed to both COPD and asthma hyperinflation, changes in lower airway bacterial coloniza-
are called mixed phenotypes. A study has shown that between tion, increased susceptibility to viral infection, and increased

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Dovepress A review of the phenotypes of AECOPD

risk from comorbid extra pulmonary diseases. However, as to exacerbators with emphysema, they respond to treatment
for the definition of frequent exacerbators, there is no uniform with Roflumilast. Selected cases with frequent exacerbations
standard at present. Most clinical research defined frequent may respond to long-term treatment with macrolides,79 and
exacerbators as those having a greater number of exacerba- when ICS cannot be used, mucolytics may be effective in
tions than the median of the study population every year, reducing exacerbations.80 However, another study shows
those needing a course of oral antibiotics or oral glucocorti- that whatever the declining degree of lung function, it is
coid therapy, or those who needed to be hospitalized twice recommended that patients with frequent exacerbations
a year because of acute exacerbations.70,71 In the ECLIPSE use ICS combined with bronchial relaxation, which can
study of COPD exacerbation susceptibility, ~20% of patients significantly reduce the number of exacerbations and improve
with GOLD stage II disease and as many as 47% of those the quality of life.81 The use of ICS is still a hot topic that
with stage IV disease were classified as frequent exacerbators needs large-scale, randomized, double-blind, controlled
(defined as two or more exacerbations annually). A previous studies in order to assess its effectiveness. In summary, the
study has shown that patients with frequent exacerbations and frequent exacerbation phenotype as a distinct phenotype is
those with infrequent exacerbations tended to remain in the of great significance and clinicians could develop a profes-
same category of exacerbation frequency for the full 3 years sional treatment for these patients, which can be used for
of the study, although a few patients may have shifted from health economic purposes.82
one category to another.70 This stability could suggest that the
frequency of exacerbations is related to the susceptibilities Discussion
of the patients. A recent review has concluded the possible The literature relating to AECOPD phenotypes in this review
reasons for the frequency of AECOPD. It concludes that high mainly focuses on the significant heterogeneity among the
levels of inflammation, high susceptibility to viral infection patients. The Anthonisen standard48 based on clinical mani-
and bacterial colonization, fast FEV1, functional decline, poor festations (published in 1987) was the most widely recog-
health care status, and worsened comorbidity will increase the nized classification in many studies and is thought to have
risk of exacerbation.72 Moreover, other studies also pointed clinical implications. Clinicians may speculate on the kind
out some meaningful factors that are related to the frequency, of etiology, draw up an individual therapy protocol, and also
as listed in Table 2. Patients with a history of frequent exac- evaluate the prognosis of patients with AECOPD according
erbations have an increased rise in both systemic inflam- to their clinical manifestations. In an in-depth study of micro-
mation and airway inflammation,73,74 more rapid decline of organisms, a respiratory infectious phenotype was classified
lung function, worse quality of life,75 and higher mortality by Dai et al8 who found that respiratory infectious phenotypes
rates76,77 compared to patients with infrequent exacerbations. are associated with a greater length of stay in hospital and
However, the classification of these frequent exacerbations greater severity of symptoms in AECOPD. However, this
phenotype is based on clinical records and/or patient recall, study did not check all the relevant factors or diseases associ-
and the history of exacerbations is provided by the patients ated with a prolonged stay in hospital, which therefore may
themselves. It is therefore important to ask about the history have affected their results. Further investigation is needed to
of exacerbations in the clinical interview in order to identify assess the clinical implication of this phenotype. In terms of
patients who may require anti-inflammatory medication. inflammatory phenotype, two studies44,46 classified AECOPD
The treatment recommended in GOLD is also different for patients with inflammatory cells or biomarkers. Neverthe-
frequent exacerbators, such as long-term inhalation of cor- less, there are some differences between the classifications;
ticosteroids. Adopting anti-inflammatory and anti-infection in the study conducted by Gao et al,44 the patients were
treatments in frequent exacerbators may be nontherapeutic. sorted into four groups, including EO, NE, PA, and MC.
In the summary of the GesEPOC,78 the frequent exacerbators They conclude that there are some differences among these
are further divided into the following two types: those with groups. While another study46 used cluster analysis to clas-
emphysema predominant and those with chronic bronchitis sify the patients into bacteria, virus, and eosinophil groups
predominant. The treatment for the two types is also different. based on biomarkers. In this study, they used two methods
For the emphysema phenotype, the basis of pharmacological to investigate biomarkers in AECOPD. The first method
treatment is long-acting bronchodilators, and in some cases used unbiased statistical tools, identified biological COPD
with ICS. The bronchitis-predominant exacerbator patients exacerbation phenotypes, and characterized exacerbations
may be treated with bronchodilators and ICS, and in contrast into four biological clusters, while the second method

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Table 2 The factors related to the frequency of exacerbations

Dovepress
Author Populations Year Location The severity Duration Outcome Definition of exacerbations
of COPD
Lin et al84 215 patients with 2011 Taibei, Taiwan Stages II to IV 3 years MBL deficiency increases the risk of recurrent A change in the patient’s baseline dyspnea,
COPD infective exacerbation cough, and/or sputum
Foreman 389 non-Hispanic white 2008 USA Stages III to IV 9 years Variants in surfactant protein B are associated COPD-related emergency room visits or
et al85 participants with COPD (postmortem with COPD susceptibility and COPD exacerbation hospitalizations

submit your manuscript | www.dovepress.com

analysis of NETT) frequency
Hurst 2,138 patients with 2010 Multicentral Stages II to IV 3 years The severity of COPD, a history of gastroesophageal Events led a care provider to prescribe
et al70 COPD (postmortem reflux or heartburn, poorer quality of life, and antibiotics or corticosteroids (or both) or
analysis of ECLIPSE) elevated white-cell count were independently hospitalization
associated with the frequency of exacerbations
Wells 3,690 COPD patients 2012 21 clinical Stages II to IV 3 years Ratio of the diameter of the pulmonary artery to the Severe exacerbation: increased dyspnea, cough,
et al86 centers in USA diameter of the aorta .1 would be associated with or sputum production or required admission.
severe COPD exacerbations Mild-to-moderate: treated with antibiotics
or systemic glucocorticoids in the outpatient
setting or during an emergency room visit
Sarinc 128 patients of COPD 2013 Turkey Stages I to II 1 year Thyroid function has an effect in exacerbation Worsening symptoms and leading to an
Ulasli et al87 frequency of COPD increase in the use of maintenance medications
Huerta 209 patients with 2015 UK Stages II to IV 8 years Upper airway symptoms increasing over time in Any change in one major symptom (dyspnea,
et al88 COPD patients with COPD are related to the frequent sputum purulence, sputum volume) with at
exacerbation phenotype least one other major or minor (nasal discharge
and/or congestion, wheezing, sore throat, and
cough) for 2 consecutive days
Morrow 248 Caucasian COPD 2015 USA Stages III to IV 1 year Myeloperoxidase was associated with the number of Requiring outpatient treatment with antibiotics
et al89 subjects recent exacerbations or oral steroids or one requiring hospitalization
Oh et al90 380 COPD patients 2014 Korea Stages I to IV 7 years Severity of emphysema, and serum lower protein Dyspnea, cough, or sputum requiring treatment
levels are the independent predictors of frequent with systemic steroids or antibiotics, a visit to
exacerbations in COPD patients the emergency room, and/or admission to a
hospital
Singh 215 COPD patients 2014 UK Stages II to IV 3 years B3GNT, LAF4, and ARHGEF10 are associated with Requiring oral corticosteroids and/or
et al91 (postmortem frequent exacerbations antibiotics or hospitalized
analysis of ECLIPSE)
Abbreviations: ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; MBL, mannose-binding lectin; NETT, National Emphysema Treatment Trial.

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Dovepress A review of the phenotypes of AECOPD

employed the currently used clinical exacerbation phenotypes a review, which is focused on answering a specific question
of COPD related to potential etiology and inflammation related solely to AECOPD.
(namely exacerbations that are associated with bacteria,
virus, or a sputum eosinophilia). The biological exacerbation Conclusion
clusters were bacterial, viral, eosinophilic-predominant, and AECOPD is a heterogeneous disease. Investigations of the
pauci-inflammatory. It was found that these clusters were different phenotypes of AECOPD have resulted in the defini-
remarkably similar to the clinical exacerbation phenotypes. tion of different types of patients with prognostic and thera-
Thus, in addition to identifying potential biomarkers to direct peutic significance. Because the diversity of the phenotypes
therapy and evaluate prognosis, these clinical exacerbation of each condition is better understood, clinicians will be
phenotypes are likely to represent distinct pathophysiological presented with opportunities to evolve from a “one size fits
entities with specific biomarker signatures. In studies con- all” approach to personalized approaches, with the ultimate
cerned with the comorbidity phenotype, Arostegui et al69 goal of improving care and reducing potential adverse
characterized the AECOPD patients into four types according effects from unnecessary therapies.83 However, research
to the severity of the current exacerbation and the comorbidi- into AECOPD phenotypes is still in its infancy, and with a
ties. Subtype D (defined as having very severe exacerbations detailed study of the phenotypes of AECOPD, it is possible
with low or mild comorbidity) was significantly related to that a new phenotype allowing individualized treatment and
mortality and admission to an intensive care unit. Although estimation of prognosis will be found. This means that there
this study did not offer detailed suggestions for the treatment is an urgent need for well-designed clinical studies focused
of AECOPD, it evoked awareness in clinicians of the need on AECOPD phenotypes.
to treat patients comprehensively. It was reported that the
frequent exacerbations were related to many factors, as is well Acknowledgment
known. The current GOLD classification of COPD acknowl- This study was supported by grants from the National Natural
edges the complexity of the disease, and the frequency of the Science Foundation of China (NSFC; Grants 81370143 to
exacerbation is also considered when classifying patients. Professor Ping Chen).
It was suggested that patients with frequent exacerbations
should have treatment with ICS. However, the definition of Disclosure
the frequent exacerbator and the subjects themselves varied The authors report no conflicts of interest in this work.
among the studies. In a retrospective study, the frequency of
the exacerbation could be influenced by the memory of the References
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