Received: 16 July 2019

| Revised: 7 November 2019

| Accepted: 3 December 2019

DOI: 10.1111/crj.13129

REVIEW ARTICLE

Risk factors of chronic obstructive pulmonary disease

exacerbations

Stanca-Patricia Hogea1 | Emanuela Tudorache1 | Ariadna Petronela Fildan2 |

Ovidiu Fira-Mladinescu1 | Monica Marc1 | Cristian Oancea1

1
Department of Pulmonology, University
of Medicine and Pharmacy “Victor Babeș”,
Abstract
Timișoara, Romania Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease
2
Internal Medicine Discipline, Medical characterised by persistent respiratory symptoms and airflow limitation. COPD
Clinical Disciplines I, “Ovidius” University
has a major impact on public health, mainly because of its increasing prevalence,
of Constanta Faculty of Medicine,
Constanta, Romania morbidity and mortality. The natural course of COPD is aggravated by episodes of
respiratory symptom worsening termed exacerbations that contribute to disease pro-
Correspondence:
gression. Acute Exacerbations of COPD (AECOPD) can be triggered by a multitude
Emanuela Tudorache, Department of
Pulmonology, University of Medicine and of different factors, including respiratory tract infections, various exposures, prior
Pharmacy “Victor Babeș”, Str. Gheorghe exacerbations, non-adherence to treatment and associated comorbidities. AECOPD
Adam nr. 13, 300310 Timișoara, Romania.
Email: [email protected]
are associated with an inexorable decline of lung function and a significantly worse
survival outcome. This review will summarise the most important aspects regarding
the impact of different factors that contribute to COPD exacerbations.

KEYWORDS
bronchiectasis, microorganisms, spirometry

1 | IN T RO D U C T ION worsening of respiratory symptoms requiring a change in

treatment COPD exacerbations are important events asso-
Chronic Obstructive Pulmonary Disease (COPD) is a chronic ciated with high impact on health status in COPD patients
respiratory disease characterised by persistent respiratory and it is well known that they are also a major determi-
symptoms and airflow limitation that is because airway and/ nant in disease progression, with inexorable decline of
or alveolar abnormalities usually caused by significant ex- lung function.2 Severe exacerbations requiring hospital-
posure to noxious particles or gases.1 COPD is an important isation are associated with a high risk of a subsequent
public health challenge and a major burden on health-care exacerbation, a rapid decline in health status and high mor-
resources.2 tality in the weeks following every severe exacerbation.6
Prevalence, morbidity and mortality vary across countries Approximately 20% of GOLD 2 patients with COPD may
and across different groups within countries. The majority of experience frequent exacerbations requiring additional
national data show an estimated prevalence of 1% in the adult treatment. The risk of exacerbations is higher for patients
population, increasing sharply in people aged ≥40.3,4 The with GOLD 3 or 4.1 Taking into account the great impact
prevalence and burden of COPD are expected to rise over the of exacerbations on the natural course of COPD, it is of the
coming decades because of continued exposure to risk factors utmost importance to recognise the risk factors associated
and the ageing of the world's population and it is predicted to with occurrence of exacerbations for a better management
become the 3rd leading cause of death by 2020.1 of these patients.
The natural course of COPD is worsened by repeated The aim of this article is to present the most common risk
episodes of exacerbations,2,5 which are defined as an acute factors and triggers involved in CPOD exacerbations and to

Clin Respir J. 2020;14:183–197. wileyonlinelibrary.com/journal/crj © 2019 John Wiley & Sons Ltd | 183
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184    HOGEA et al.

discuss their importance in accordance with the degree of ex- and Acinetobacter spp. (2.94%). They also concluded that
acerbation severity. hypercapnic respiratory failure, advanced age and systemic
steroid use are independent risk factors for isolation of K
pneumoniae and P aeruginosa.
2 | M IC ROO RGA N IS MS A recent Korean study that analysed 736 cases of severe
AECOPD found a direct correlation between the severity of
The most common causes of AECOPD are respiratory in- bronchial obstruction and the bacterial identification rate,
fections.2,7 Bacteria are responsible for 40%-60% cases of with P aeruginosa and S pneumoniae showing the stron-
respiratory infections, viruses for about 30% and atypical gest association (P = 0.011 and P = 0.048 respectively).
bacteria for 5%-10%.8 Pathogens were identified in 63.3% of cases and the most
The most frequent bacterial pathogens involved in common isolated bacterial pathogens were Pseudomonas
AECOPD occurrence are Streptococcus pneumoniae, aeruginosa (13.0%), Streptococcus pneumoniae (11.4%)
non-typeable Haemophilus influenzae and Moraxella ca- and Haemophilus influenzae (5.3%). S aureus and K pneu-
tarrhalis.3 Polymicrobial cause may affect up to 33% of moniae were more frequently isolated in the mortality event
AECOPD cases.9 However, these results were reported group (P = 0.003 for S aureus, P = 0.009 for K pneumo-
among outpatients by using different methods for obtaining niae).20 Another study showed a higher rate of Haemophilus
the respiratory secretions for bacterial culture across different influenzae isolation (23.9%) among 92 hospitalised patients
studies (sputum, protracted specimen brush). Furthermore, with AECOPD, while Acinetobacter baumannii and P aeru-
the bacteriological profile of the causative agent is different ginosa positive cultures were associated with prolonged
in hospitalised patients, who usually have a more severely hospitalisation and severe airway obstruction (P = 0.03 and
affected lung function, and the spectrum of the causative or- 0.031 respectively).21 In fact, other studies have also demon-
ganisms is different.10 Moreover, there is a large variety of strated the correlation between the severity of airway obstruc-
bacterial species that could not be cultured with available tion and the type of microorganisms isolated in AECOPD
conventional technique,11 and, also a geographical diversifi- patients.9,22,23 Pseudomonas aeruginosa and enteric Gram-
cation in the spectrum of the aetiological bacteria.3 negative bacilli are more frequently found in patients with
Studies involving lung microbiome in patients with severely impaired lung function and severe exacerbations
COPD demonstrated the presence of potentially pathogenic that require mechanical ventilation.9 Rodrigo-Troyano et al
bacteria (PPB) colonisation in the bronchial tree.10,12 Non- showed in their study involving COPD patients with a me-
typeable Haemophilus influenzae is the most common bacte- dian FEV1 of 36% (±17) of predicted value, that 13% of them
rium found in distal airways of COPD patients both in stable had a positive P aeruginosa sputum culture and its presence
periods and in exacerbations.13 was associated with higher mortality.22
Patients with COPD have significant impairment of lung Fungal colonisation and its potential role in AECOPD are
defence mechanisms, with direct consequence of PPB pro- poorly understood. In a recent research it was observed that
liferation in their bronchial secretions.3 During COPD exac- the presence of colonisation with Aspergillus fumigatus can
erbations there are important changes in the composition of aggravate airway hyperresponsiveness and induce sustain-
lung microbiome, but not in microbial community structure.12 able airway inflammation and bronchoconstriction. Thus, the
In several recent studies researchers have reported relatively article suggested that Aspergillus colonisation may increase
uniform changes in community composition of microbiome the severity of exacerbations in COPD patients.24
across subjects, with an increase in the relative abundance of Viral infection is considered to be one of the most im-
specific taxa, especially members of the Proteobacteria phy- portant risk factors for AECOPD, being responsible for
lum, including non-typical COPD pathogens.14-17 about 25% of the COPD exacerbations during all seasons.25
While Haemophilus influenzae and Moraxella Catarrhalis The most common viruses reported to be associated with
have more frequently been reported as common pathogens AECOPD are Rhinovirus, Influenza A, Respiratory syncytial
involved in exacerbations occurring in patients with mild to virus (RSV) and Parainfluenza. Similar to the bacterial infec-
moderate forms of COPD, the bacteriological spectrum is tions, geographic variations were reported in the overall viral
different for severe COPD patients that have chronic bron- prevalence among AECOPD, but also, in the contributions of
chitis and/or bronchiectasis.9,10,18,19 In a prospective study of each virus pathogen.26,27 While Rhinovirus was the most fre-
bacteriological aetiology of hospitalised AECOPD patients,10 quent virus isolated in the western countries, Influenza was
the authors reported that bacterial pathogens were isolated in the most common viral pathogen detected in Korea.
almost half (47.22%) of the cases, of which Pseudomonas Contrary to the bacterial infection, the viral identifica-
aeruginosa was the most predominant organism (38.23%), fol- tion rate tended to be lower at more advanced COPD stages
lowed by Klebsiella pneumoniae (29.41%), Staphylococcus (P = 0.031).20 In an Australian study, the authors found simi-
aureus (23.53%), Streptococcus pneumoniae (5.88%) lar virus spectrum in AECOPD patients with the one reported
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HOGEA et al.    185

in adult general population. They also reported the presence non-exacerbator phenotypes (58.91% in emphysema and
of virus and bacteria co-infection (Pseudomonas aeruginosa, 57.67% in chronic bronchitis phenotype, P = 0.03).34
Haemophilus influenzae and Aspergillus species) in 22% of Furthermore, a recent study has demonstrated an in-
cases.28 creased cell-surface expression of ICAM-1 (major receptor
Respiratory viruses were detected in 19.7% of 233 hospi- for 60% of human rhinoviruses and Haemophilus influenza)
talised patients with AECOPD in India, influenza A/H3N2 in the airway epithelium of smoker patients with chronic
and rhinoviruses being the most common viruses detected.29 airflow limitation. These results may underline the relation
In an Iranian study performed over a 3-year period in order between active smoking, infection and frequency of exacer-
to eliminate bias to seasonality, the presence of viral infection bations.35 However, there are conflicting data regarding the
was detected in 47.6% of patients with COPD exacerbations association between active smoking and susceptibility to ex-
and in 25% of stable COPD patients (P < 0.05). Rhinovirus was acerbations, this relation disappeared after multivariate anal-
the most common virus observed in both groups of patients, yses in some studies36,37 and remained present in others.38
followed by RSV A/B, Adenovirus, Enterovirus and Influenza Over the past decade, the relation between air pollution expo-
A virus. In addition, this study evidenced dual viral infection sure and AECOPD has been investigated in several studies,
present in 22.2% of AECOPD patients. Besides the respiratory but the results were non-conclusive. Some epidemiological
symptoms, the patients with viral exacerbation presented more studies have demonstrated that short-time exposure to air pol-
frequent non-respiratory symptoms (fever, muscle pain) and a lution significantly increased the risk of exacerbations,5,39,40
longer symptoms remission time (15 days vs 9 days).30 whereas others found no causality41 or association with only
The seasonal pattern of COPD exacerbations described for selected pollutants.42-44
in the TORCH study31 was also demonstrated in other stud- The major pollutants shown to affect the respiratory sys-
ies.25,26 Most viral infections usually occur in winter, fol- tem are represented by: ozone (O₃), carbon monoxide (CO),
lowed by summer, autumn and spring. particulate matter (PM2.5, PM10) and sulphur dioxide (SO₂).
The impact of vaccination on the occurrence of AECOPD These pollutants could induce oxidative stress and inflamma-
was studied by Kwak et al,26 who reported a similar vaccina- tion, resulting in airway injury and dysfunction.45
tion rate against influenza virus between viral infection and A large longitudinal epidemiologic study investigated
non-viral infection group. However, among the group with the effects of air pollutants on COPD admissions in Beijing,
viral infection, the patients with influenza infection had a China, between 2013 and 2017. Significant effects on hos-
lower rate of influenza vaccination than those with the other pital admission for exacerbation of COPD were observed
viral infection. In this study the authors also found that fe- for SO2, NO2, CO, PM2.5 and PM10 but not for O3. Higher
male subjects are at a significantly higher risk for viral infec- risk effect was found during warm seasons. For NO2, CO,
tions in COPD exacerbations. PM2.5 and PM10, the risks were slightly larger in males and
the elderly.46
Li et al conducted a meta-analysis of short-term air pollu-
3 | S M O K ING A N D A IR tion exposure and risk of AECOPD and found an increased
PO L LU TIO N probability of COPD exacerbation risk with exposure to all
gaseous and particulate pollutants, especially NO2 and O3.
Smoking is widely recognised as the major risk factor for The correlation between NO2 and SO2 short-term exposure
COPD development and progression. Smokers have a faster and AECOPD risk seemed to be more pronounced in low-/
decline in lung function and a higher mortality rate than middle-income countries than in high-income countries.
non-smokers.1,32 They also observed that NO₂ and O₃ play a role in acute
The results of a study of more than 2.000 COPD patients in respiratory attack and CO was strongly associated with
the United States, followed for a 5-year period, demonstrate that seasonality.45
the decline in FEV₁ among current and intermittent smokers In the last years, there has been increased attention to
is higher than among former smokers (9-mL decline vs 2-mL the effects of particulate matter (PM) aerosols on respira-
decline; P = 0.005 for difference). For patients with GOLD 2 tory morbidity, especially on COPD exacerbation risk. A re-
and 3 stage, the loss of lung function was steeper over time for cent study showed that for every 10 μg/m3 increase in PM10
current and intermittent smokers with a severe acute exacerba- levels, the COPD emergencies increased by 3.34% and by
tion compared with former smokers or patients without severe 3.75% in individuals over 74 years of age.42 Another study
AECOPD or both (57 mL/y vs 18 mL/y; P < 0.0001 for GOLD found a 2.5% increase in hospital admissions because of
stage 2; 39 mL/y vs 10 mL/y; P = 0.008 for GOLD stage 3).33 COPD exacerbation for every 10 µg/m3 increase in PM10.47
In a Spanish observational, cross-sectional, multicentre In addition, a meta-analysis of 18 studies of PM10 and
study of over 1.600 COPD patients it was showed that ac- AECOPD showed that a 10 µg/m3 increase in daily PM10
tive smoking is more frequent among exacerbator than in was associated with a 2.7% increase in hospitalisation for
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186    HOGEA et al.

AECOPD.48 Several studies have examined the combined A recent Portuguese study59 analysing the 5-year predic-
effect of air pollution and temperature on COPD exacerba- tion of the combination of exacerbations, hospital admissions
tions, and the results were inconsistent.49-51 For instance, and mortality in stable COPD patients, previous year exac-
Ding et al49 demonstrated a significantly higher risk of hos- erbation represented the best predictor of the future risk of
pital admission for COPD patients on higher temperature exacerbations, independent of severity. During the 5-year
polluted days, while other studies50,51 reported increased ef- follow-up, almost 70% of GOLD C patients and almost 90%
fect on cold days. A study carried out in Taipei showed that of GOLD D patients suffered exacerbations. More than 67%
increased admissions for COPD were associated with PM2.5 of hospitalisation and mortality because of AECOPD were in
both on warm (>23°C) and cool (<23°C) days, and also, a group D COPD patients.
direct correlation between the length of hospitalisation and Margüello et al demonstrated that the history of exacerba-
the levels of PM2.5.52 tions in the previous year is the most important independent
As to the indoor pollution and the risk of COPD exac- predictor of exacerbations in the following year. They also
erbations, there are few data to document this association. highlighted that 85.5% of patients with frequent exacerba-
Hansel el al found that a 10 μg/m3 increase in PM2.5 indoor tions in the previous year had at least one exacerbation in
concentration raised the odds of a severe AECOPD occur- the subsequent year. Prior exacerbations had a sensitivity of
rence by 38%.53 51.9% and a specificity of 85.8% for the frequency of the ex-
acerbation in the following year. The frequency of AECOPD
in the previous year was the most important independent pre-
4 | S E A S ONA L VA R IAT IO N S dictor of severity of “frequent exacerbations” in the following
year.60
There are few published data regarding the role of tempera- The exacerbation history is one of the most important risk
ture on AECOPD occurrence, all of which showing a strong factors for hospitalisation, death and future exacerbations.
association between the number of AECOPD and seasonality The risk for AECOPD is also directly correlated with age and
both in the northern and in the southern hemisphere. Similar with lung function impairment. Patients who had more exac-
with the published results of the TORCH31 and POET54 tri- erbations in the past have a higher risk of exacerbations in the
als, other studies also found an increased number of hospi- future, an accelerated decline in lung function and quality of
talisations for COPD during winter months.55-57 life and an increased risk of death.61,62
In a Spanish study,57 the highest hospitalisation rate for
AECOPD was in winter (37.6%), followed by autumn (24%),
spring (23.7%) and summer (14.6%). The number of hospi- 6 | SEVERE AIRFLOW
tal admissions for COPD was closely and independently re- LIM ITATION
lated to the mean temperatures, with an increase of 4.7% for
each Celsius degree decrease in mean weekly temperature The relationship between COPD exacerbation and the degree
(r(2) = 0.599, P < 0.001). of airflow limitation was demonstrated by several studies.63-67
Analysing the seasonal variations in mortality and exac- A recent 3-year study published in the Netherlands, which
erbations in COPD patients during the TIOSPIR trial, Wise included 795 COPD patients with a lower FEV1% predicted
et al found clear differences among the percentage of was associated with a higher risk of hospital admission for
AECOPD occurring in winter (34.1%), autumn (26.3%), a severe AECOPD with an HR of 2.0 (95% CI 1.4-2.5) for
spring (23.2%) and summer (16.4%). Severe exacerbations patients treated with tiotropium respectively an HR of 2.04
(19.6% of all exacerbations) were more common in winter (95% CI 1.43-2.50) for ICS treated patients. Furthermore,
(35.4%) and less common in summer (16%). Although the re- a lower FEV1% predicted at baseline was associated with a
spiratory hospitalisation because of severe AECOPD peaked higher mortality risk.63
midwinter, the respiratory deaths were more frequent in early Müllerová et al demonstrated that the risk of frequent ex-
spring. In the southern hemisphere there were no significant acerbations increased with higher severity of airway limita-
differences between the frequency of exacerbations during tion (OR = 1.2 for moderate limitation and OR = 2.4 for very
winter (28.5%) vs summer (22.3%).56 severe limitation).64
A study developed in Hong Kong showed that 77% of hos-
pital admissions were for patients with COPD with moderate
5 | P R IO R E X AC E R BAT ION S to severe airflow limitation.65
Montes de Oca et al revealed an increased number of med-
According to both older and newer published research, the ical visits directly correlated with the airflow obstruction se-
most consistent predictor of COPD exacerbations is a previ- verity and dyspnea,66 while Foda showed that an increased
ous history of exacerbations.37,58-62 airway obstruction determined a more severe AECOPD.67
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HOGEA et al.    187

7 | B IO M AR KE R S with history of AECOPD (P = 0.006) than low-level fibrino-

gen (<350 mg/dL) group.77
7.1 | Eosinophilia Another publication that analysed the data obtained from
five studies evidenced that high fibrinogen was associated
The eosinophil count is a marker for eosinophilic airway in- with an increased risk of hospitalised COPD exacerbations
flammation and a predictive biomarker for the efficacy of ICS within 12 months (HR: 1.64; 95% CI: 1.39-1.93) among
treatment in patients with COPD exacerbations.68-70 COPD participants in the Atherosclerosis Risk in Communities
patients with eosinophilia (≥2%) have an increased risk of Study (ARIC), the Evaluation of COPD Longitudinally to
AECOPD.5,70-73 The first study to investigate the prevalence of Identify Predictive Surrogate Endpoints (ECLIPSE) study
blood eosinophilia (defined as ≥300 cells/L) among inpatients and the Cardiovascular Health Study (CHS). Also, elevated
with AECOPD evidenced a higher frequency of exacerbations fibrinogen was associated with an increased risk of death
during the 1-year follow-up period compared to patients with- within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all
out eosinophilia.68 Higher blood eosinophil cell count (≥200 participants.78
cells/µL and/or ≥2%) at admission for an AECOPD is associ- Fibrinogen may be a useful biomarker to identify indi-
ated with increased COPD readmission rates even in patients viduals with COPD and a high risk of future exacerbations
with infrequent COPD hospitalisations.72 The same cut-off of and may detect those with a higher risk of mortality. Also,
eosinophils during the first hospitalisation for an AECOPD was it could be a useful biomarker for enriching clinical trials in
shown to predict increased susceptibility to up to two readmis- the COPD population. Attenuation of systemic inflamma-
sions.73 A recent meta-analysis demonstrated a significantly de- tion may offer new perspectives in the management of pa-
creased risk for acute exacerbation in favour of ICS-containing tients with COPD, thus reducing the burden and frequency of
treatments vs non-ICS/ICS withdrawal/placebo treatments in exacerbations.76,78,79
patients with ≥2% blood eosinophils (RR, 0.81; 95% CI, 0.67- At present, fibrinogen is the first biomarker drug develop-
0.99; P = 0.03). However, the risk of pneumonia was also in- ment tool qualified for use in COPD under the FDA's (Food
creased in COPD patients with higher eosinophil counts who and Drug Administration) drug development tool qualifica-
used ICS treatment.70 tion programme.80
Another systemic review, that included ten studies, with a
total of 85.059 COPD patients, evaluated the risk of AECOPD
among patients with elevated blood eosinophil counts treated 7.3 | IgG deficiency
with ICS vs non-ICS treatment. They found an overall re-
duction risk of moderate or severe exacerbation in patients Only a few articles have described the association between
with blood eosinophilia and ICS treatment (RR, 0.77, 95% the IgG subclass deficiencies and COPD exacerbation
CI, 0.73-0.81). Also, this study evidenced an increased risk risk.81-83 Using samples from two large COPD trials,84,85
of exacerbations following the de-escalation of ICS treatment Leitao Filho et al found that reduced total IgG levels are
(RR, 1.66, 95% CI, 1.31-2.10).74 These results show us the associated with increased risk of AECOPD and hospitalisa-
benefits of ICS treatment in this group of patients. tions, with the greatest risk observed among participants with
total IgG levels <7.0 g/L.82 Furthermore, they revealed that
approximately 1 in 5 COPD patients had one or more IgG
7.2 | Fibrinogen subclass deficiencies and reduced IgG1 or IgG2 levels were
associated with increased risk of AECOPD, but only IgG2
Fibrinogen is a marker of systemic inflammation and may remained as an independent predictor of hospitalisations.
be important in the pathogenesis of COPD.75 More studies Lower IgG1 and IgG2 levels were detected in patients who
demonstrated that a high fibrinogen levels (≥350 mg/dL) in developed two or more exacerbations during follow-up.83
patients with COPD was associated with an increased risk of Two case series of Ig treatment for patients with frequent
AECOPD.76-79 COPD exacerbations, who presented an underlying primary
Groenewegen et al evidenced in a study that of the inflam- antibody deficiency syndrome, reported a markedly reduced
matory markers measured only fibrinogen was associated number of exacerbations and, also, of hospitalisation rate for
with the number of moderate exacerbations in the follow-up AECOPD.86,87
period. Multivariate analyses showed that elevated fibrino-
gen levels is an independent risk factor for AECOPD.76
A study developed in Korea showed that high fibrinogen 7.4 | Vitamin D deficiency
level was independently correlated with poor COPD assess-
ment test score (P < 0.001) and an experience of exacerba- A high prevalence of vitamin D deficiency in patients with
tion (P = 0.033). The high-level group had more patients COPD has been reported by several studies.88-90
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188    HOGEA et al.

Severe deficiency (vitamin D levels <8.65 ng/mL) was (14.9%). Mortality was higher in patients with systolic dys-
found to be associated with frequent COPD exacerbations function (19.2%) compared with subjects who had preserved
and hospitalisations. This association is independent of pa- ejection fraction (4.8%).96
tient characteristics and comorbidities.88 Vitamin D supple- In a large-scale study Jones et al97 investigated the correla-
mentation could reduce COPD exacerbation rates.88,91 tion between CVD and exacerbation rates and mortality in
COPD cohort. They concluded that the presence of CVD was
not associated with increased risk of exacerbations or death,
8 | A ST H MA-CO P D OV E R LA P but with a higher risk of hospitalisation. From a total number
of 2887 COPD, 48% also suffered from CVD. These patients
In recent years, asthma-COPD overlap (ACO) is of consider- were older, but had a similar severity of the airflow limitation
able interest worldwide as it is associated with worse health and exacerbation history to those without CVD. Moreover,
outcomes compared with COPD or asthma alone.92-94 no particular CVD was associated with an increased inci-
A systematic review conducted by Nielsen et al concluded dence of AECOPD. Followed up for 24 months, among those
that ACO patients had more frequent and more severe exacer- with or without CVD, there was no difference regarding the
bations compared to patients with asthma and COPD only.92 annualised rate of AECOPD. However, patients with CVD
A retrospective study carried out in Taiwan showed that had a 51% higher rate of severe exacerbations, which required
patients with ACO had more exacerbations (35.3%) than pa- hospitalisation, compared with those with no CVD.
tients with asthma (29.0%, P < 0.0001 vs ACO) or COPD Some studies showed that patients with COPD have a
alone (18.6%, P < 0.0001 vs ACO). ACO patients had a higher risk of myocardial infarction (MI), especially after ad-
higher rate of exacerbations requiring emergency room vis- mission periods.98-100 Rothnie et al evidenced that patients
its (8.2% vs 2.7% for the patients with COPD, P < 0.0001 with AECOPD have a higher risk for MI and ischemic stroke.
and 2.3% for the asthma patients, P < 0.0001) and inten- Compared with stable periods, the risk of MI increased with
sive care unit treatment (4.3% vs 2.7% for the patients with 65% and with 51% for ischemic stroke in the 4 weeks after
COPD, P < 0.0001 and 0.5% for the patients with asthma, an AECOPD. Infrequent exacerbators had a higher risk of
P < 0.0001).93 MI (69% higher rate) compared with the stable periods,
Similar results were reported by other studies.66,92-94 while frequent exacerbators had a lower risk of MI (42%,
Montes de Oca et al66 evidenced that the number of exac- P = 0.009). The risk for ischemic stroke was 68% higher in
erbations was 4.9 times higher in patients with ACO, while those with infrequent exacerbations compared with frequent
Kang et al94 found that these patients suffered more frequent exacerbators (30% higher rate, P < 0.001). Patients with se-
and more severe exacerbations, resulting in a higher number vere exacerbations had a higher risk of ischemic stroke.101
of hospital admissions. Serra-Picamal et al investigated the profile of patients
hospitalised for AECOPD and defined a “fragile COPD pa-
tient” as an older male, with frequent CV co-morbidities and
9 | CO M O R B ID IT IE S a history of previous hospitalisations for reasons other than
COPD. These subjects required prolonged hospitalisation
9.1 | Cardiovascular disease and had a higher readmission rate.102
These findings were also supported by a review which
Cardiovascular disease (CVD) is a common comorbidity in showed that comorbidities such as cardiac failure, ischemic
patients with COPD. They often associate ischemic heart heart disease, pulmonary hypertension, diabetes, anxiety, de-
disease, arrhythmias, heart failure and the arterial circulation pression, GERD and asthma are associated with an increased
diseases. The presence of CVDs in the COPD group is asso- risk for severe exacerbations requiring hospitalisation. A pa-
ciated with increased likelihood of mortality, of unfavourable tient with COPD also suffering from cardiac failure or isch-
outcomes, a higher rate of hospitalisations and a low quality emic heart disease would be twice more likely to be admitted
of life.64,95 than another patient not having these comorbidities. They
Heart failure may mimic AECOPD and the presence of concluded that these associated conditions do not appear to
this comorbidity is an independent predictor of mortality. be risk factors for frequent exacerbations, rather than an in-
Atrial fibrillation can be a consequence or a trigger of an creased risk for severe, life-threatening AECOPD that can
AECOPD episode. High blood pressure represents the most result in admission and death particularly in older subjects.103
frequent comorbidity in patients with COPD. Diastolic dys- In the SPIROMICS cohort the baseline NT-proBNP was
function may mimic the symptoms of an acute exacerbation.1 an independent predictor of AECOPD, even in individuals
Andrijevic et al reported that the most common CVDs as- without diagnosed CVD. The impact of detection and treat-
sociated with AECOPD were arterial hypertension (77.8%), ment of early cardiovascular dysfunction on COPD exacer-
systolic dysfunction (24.2%) and coronary artery disease bation frequency warrants further investigation.104 There is a
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HOGEA et al.    189

higher prevalence of carotid atherosclerosis in COPD than in reflux or heartburn.111 The presence of gastroesophageal reflux
control smokers or former smokers.102,105 disease (GERD) in COPD patients is associated with a seven
time greater risk of AECOPD and a higher rate of hospitalisa-
tion or emergency room visits.112-114 There are several possible
9.2 | Bronchiectasis mechanisms by which GERD may influence the severity of
COPD and the exacerbation rate. First, gastric acid microaspi-
Several studies showed that the association of bronchiectasis ration induces a laryngeal or tracheal irritative response which
(BE) and COPD determined more frequent and severe exac- results in vagally mediated bronchoconstriction, cough, dysp-
erbations, with a longer duration, impaired quality of life and nea or wheezing and is followed by an inflammatory reaction
reduced survival.19,71,106 Association of these two diseases is with a systemic cytokine spill over. It has also been suggested
more frequent in patients with severe airflow limitation.19,71 that non-acid reflux may also play an important role in va-
A study regarding the relationship between the pres- gally mediated bronchoconstriction.113 Second, GERD is also
ence of bronchiectasis and acute exacerbation in Thai known to be associated with an increased bacterial load and
COPD patients showed that frequent AECOPD exacer- colonisation of lower airways which increases the sensitivity to
bations of ≥2 year or at least 1 hospitalisation in the pre- inflammation, infection and AECOPD.115,116 On the contrary,
vious year were associated with bronchiectasis (OR 4.99; there is a high prevalence of hiatus hernia because of chronic
95% CI: 1.31-18.94; P = 0.018). Labaki noted that 28.3% cough in COPD individuals. Also, bronchodilators induce gas-
of respiratory exacerbations in the entire COPD cohort can trointestinal smooth muscles relaxation which facilitates reflux
be attributed to bronchiectasis and 45.4% of AECOPD in and theophyllines stimulates gastric acid production.114
patients with bronchiectasis can be attributed to their bron- Lee et al examined the microaspiration of gastric contents
chiectasis.107 Positive bacterial culture was identified in and identified pepsine in sputum samples in 33% of patients
12.5% of cases. The most common isolated microorganisms with moderate-severe COPD. Laryngopharyngeal reflux has
were Pseudomonas aeruginosa (4.16%) and Acinetobacter also been detected in 44% of patients, based on symptom
baumannii (4.16%).106 Chronic pathogenic colonisation, es- questionnaires and laryngeal examination. They concluded
pecially with Pseudomonas aeruginosa, present in patients that patients who had both nocturnal and daytime GERD
with COPD and bronchiectasis, is considered a potential symptoms and who did not use regular acid inhibitory treat-
mechanism for frequent AECOPD.5 ment had a higher risk for more exacerbations. On the con-
Minov et al identified a shorter duration of exacerbation- trary, the high prevalence of asymptomatic reflux (20%-74%
free interval (expressed in days) in patients with COPD and of COPD patients) underline the importance of screening of
associated bronchiectasis than patients with COPD without GERD in this population.112
BE (ranging from 37-82 days vs 49-88 days, P = 0.0149).71 A multivariate logistic regression analyses revealed that
Another recent research in Spain108 analysed the char- GERD was an independent risk factor of AECOPD. This
acteristics of men and women hospitalised with AECOPD association was independent of other potential exacerbation
during 2006-2014 according to the presence or absence of risk factors such as respiratory infection, degree of airway
bronchiectasis. 5.09% of hospitalised patients with AECOPD obstruction, congestive heart failure, cardiac medications,
had concomitant bronchiectasis, with a higher frequency poor adherence to medical therapy or older age.113,117
in men and older persons. Regarding isolated microor- An early reflux diagnosis can eliminate a modifiable risk
ganisms, a greater proportion of infections with P aeru- factor for AECOPD. A 12-month trial of proton pump inhib-
ginosa and Aspergillus species was found in patients with itors (PPI) therapy in COPD patients with GERD, revealed
AECOPD and bronchiectasis. Duration of hospitalisation, a reduced AECOPD frequency compared to usual care.117
cost and number of readmissions were higher in COPD pa- Antireflux surgery should be considered when pharmaco-
tients with bronchiectasis than in those without, while crude logical management fails. Applied in patients with severe
in-hospital mortality was significantly lower. COPD, awaiting transplantation, showed a reduction of both
Several studies reported an increased risk for mortality GERD and lung disease symptoms.112,118
among COPD patients with comorbid bronchiectasis.19,109,110

9.4 | Mental disorders

9.3 | Gastroesophageal reflux disease
Anxiety and depression are commonly associated with
The prevalence of both proximal and distal reflux is five times COPD and have a negative effect on exacerbations.5 Among
higher in COPD subjects than in non-COPD populations. In COPD patients the prevalence of depression varies between
the ECLIPSE study, the best predictors for AECOPD, across 6% and 50% and of anxiety between 10% and 15.8%, depend-
all GOLD stages, were previous exacerbations and history of ing on diagnostic methods.119 Moreover the prevalence of
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190    HOGEA et al.

depression in COPD patients increases with the disease se- patients with COPD express a cognitive impairment that
verity therefore 60% of long-term oxygen therapy recipients could easily be assessed by different questionnaires and tests.
are suffering from this comorbidity. They are correlated with A study showed that in patients with AECOPD these ques-
an increased risk of re-admission for AECOPD of COPD tionnaires scores were significantly altered compared to the
and have negative effects on therapeutic adherence.119,120 one recorded in patients with stable COPD and controls.124
Chronic psychological stress may weaken the immune sys- According to Gemma el al 48.5% of hypoxic patients with
tem and may increase the susceptibility to respiratory infec- COPD showed a particular cognitive impairment pattern,
tions and AECOPD.119 characterised by a sever deterioration of verbal and verbal
Montserrat-Capdevila et al showed that 15.6% of pa- memory tasks and diffuse diminishing of the other func-
tients suffer from anxiety and depression (7.2%-anxiety and tions.125 Another study regarding the influence of hypoxia
12,5%-depression). The incidence of hospitalisation was greater on mental status of COPD revealed compromised executive
in patients with COPD and anxiety/depression (26.3% vs functions, a decline in attention and a slower processing
13.4%). Also they highlighted that mental disorders increased speed.126 All these have a negative impact on treatment ad-
the risk of hospitalisation by almost double over the two years herence, self-management, exacerbation rate and mortality.
of the study (P < 0.041).119 Iyer et al investigated the role of
depression in both short and long-term readmission. Out of 422
patients with AECOPD, 131 patients (31%) associated depres- 9.5 | Pulmonary embolism
sion and 89 patients (21%) associated anxiety. These patients
were divided in two groups based on 1-year readmission rate: A metanalysis investigated the prevalence of pulmonary em-
132 as readmitted and 290 as non-readmitted. Those readmit- bolism in unexplained AECOPD. They reviewed 22 articles
ted had a lower FEV1, a higher prevalence of GERD and more and included 7 studies. From a total of 880 patients with un-
frequent depression (47.7% vs 23.4%; P = 0.001) and anxiety explained AECOPD, the pooled prevalence of pulmonary
(28.8% vs 17.6%; P = 0.009). Moreover, they highlighted that embolism was 16.1%. The most common localisations of
11% of patients were readmitted within the first 30 days, 5% trombembolism (68%) were main pulmonary arteries, lobar
were readmitted between days 31-90 and 15% were readmit- or interlobar arteries and had a clear indication for anticoagu-
ted between days 91-365. The global hospitalisation rate was lant treatment. This condition should be suspected in subjects
31% in the first year. Depression was associated with increased with unexplained AECOPD especially when they present
30-day hospitalisation (OR = 4.31, P < 0.001) and remained pleuritic chest pain and signs of cardiac failure and no clear
high after multivariable adjustment (OR = 3.83, P < 0.001). evidence of infections.127
They also showed that anxiety increased the risk of 30-days
readmission (OR = 2.65, P = 0.003). Anxiety and depression
frequently coexist, and the latter appears to be a stronger pre- 9.6 | Diabetes
dictor for readmissions.120
Depression reduces quality of life, the level of physical Patients with COPD have a relatively increased risk of de-
activity and is associated with higher rates of COPD exac- veloping diabetes. The prevalence of metabolic syndrome
erbation and increased mortality.111,121,122 Because both according to studies, is around 22.5% of COPD patients.
depression and anxiety are potentially modifiable risk fac- Diabetes has a negative impact on the COPD evolution by
tors, they may be valuable targets for interventions aiming shortening time to first sever EACOPD requiring hospitali-
to reduce AECOPD rates. Patients with anxiety and depres- sation, by increasing hospitalisation time and by increasing
sion have low self-confidence and self-efficacy that can lead the risk of death during exacerbations. The sputum culture of
to less disease-related coping mechanisms and poor self- COPD patients, in the presence of diabetes, is also associated
management. They have low adherence to medical treatment, with the isolation of more aggressive bacteria.103,111,128-131
pulmonary rehabilitation programmes and smoking cession.
Retrospective studies found antidepressant medication to be
correlated with significantly lower mortality rate in these 9.7 | Obstructive sleep apnoea syndrome
subjects.123 Therefore, diagnosis and early treatment of these
comorbidities has an important role in improving adherence Contrary to what was previously believed, the prevalence
to treatment and in decreasing the number of AECOPD. of obstructive sleep apnoea syndrome (OSAS) is not higher
Another comorbidity that has gained interest lately is in COPD than in the general population. However this con-
cognitive impairment. This can partially be explained by the dition is associated with an increased risk of death among
potential neuronal damage mediated by hypoxia or by other COPD patients, because of more frequent exacerbations.
comorbidities that alter the nervous system, such as vascular Furthermore, OSAS leads to a higher risk of developing CVD
disease and smoking. Compared with age-matched controls, such as pulmonary hypertension or right heart failure.131,132
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HOGEA et al.    191

9.8 | Skeletal muscle weakness to GOLD strategy. Moreover, GOLD-adherent prescribing

lead to moderate benefits on COPD symptoms and health-
The prevalence of skeletal muscle weakness increases with care resources utilisation, but no significant improvement
the severity of respiratory disease. A vicious circle is com- on exacerbations. On the contrary, under-treatment was cor-
monly developed, the skeletal muscle weakness leading to related with a significant escalation of symptoms, and both
reduced endurance and exercise capacity, sedentarism, low under-treatment and over-treatment were correlated with in-
quality of life. Moreover, skeletal muscle weakness is as- creased health-care resources utilisation.
sociated with an increased risk for more sever exacerba-
tions, longer hospitalisation periods, increased health-care
utilisation and increased hospital re-admission rate after an 11 | AGE OF PATIENTS AND
exacerbation.133 BODY M ASS INDEX

Several studies showed that older age and low body mass
9.9 | Chronic kidney disease index (BMI) were associated with higher rate of acute exac-
erbation episodes.138-141 A large study carried out in Scotland,
The coexistence of COPD and chronic kidney disease (CKD) which included 3342 patients with COPD that had been fol-
is more common in older people. CKD is a risk factor for lowed for a long period of time (median 1.9 years) showed
mortality in patients with COPD and levels of albumin-to- that the increasing age and a low BMI were associated with
creatinine ratio is associated with all-cause mortality in poor outcome.139 A retrospective study conducted by Hunter
these patients. Also, patients with COPD who begin dialy- et al138 showed that older age patients and patients with low
sis have a higher risk of mortality and lower rates of kidney BMI presented an increased risk of first AECOPD admission
transplantation.134 after diagnosis. Furthermore, they observed that high BMI
was associated with reduced risk of both first AECOPD ad-
mission and readmission.
10 | NO N -AD HE R E NC E TO A Spanish study that included 2501 patients over a 3-year
TR E AT M EN T period, showed that older patients had at least one episode of
exacerbation during the follow-up period. In their study an
The effects of inhaler drugs are influenced by patient's over 68 age was the second predictor factor of future risk of
compliance to medication. A better adherence to treatment exacerbations in the history of exacerbations.141
reduces the risk of hospitalisation and death because of Oostenbrink et al obtained the same results; a low BMI was
AECOPD. Koehorst-ter Huurne et al63 showed that patients significantly associated with an increased risk of hospitalisa-
with suboptimal use, under-use or over-use of tiotropium had tion. Patients with a BMI lower than 18.5 had a 3.6-fold greater
an increased risk for severe AECOPD, for pneumonia and risk of hospitalisation than patients non underweight.140
a higher mortality compared to patients with optimal use of It is known that COPD is an age related-disease. In some
treatment. A study analysed the exacerbation rates in 13 657 situations, it is difficult to diagnose COPD in elderly popu-
COPD patients, during a 12 month period after inhaled corti- lations because they often associate an increased number of
costeroid/LABA treatment was initiated. Researchers found comorbidities. These patients may experience atypical symp-
that only 13.9% of the subjects were adherent during follow- toms, such as muscle weakness, vertigo, confusion and leg
up. The moderately and highly non-adherent patients had oedema during severe exacerbations. Spirometry plays an
higher exacerbation rates and health-care costs than the ad- important role in the diagnosis of COPD, but elderly patients
herent individuals.135 may be unable to satisfactorily perform this test. For this rea-
Another study on the impact of patient satisfaction with son COPD remains underdiagnosed and undertreated in the
their inhalers on treatment adherence revealed a small but older people. Therefore this disease has a dramatically impact
significant association between increased treatment adher- on the health status of these patients.142
ence and a lower exacerbation rate (R2 Z 0.037; P < 0.001) A prospective observational study which included elderly
respectively fewer hospitalisations because of exacerbations people (mean age—87.0 ± 4.9 years) evidenced that in-hospital
(R2 Z 0.025; P < 0.001). Moreover, there was a correlation mortality was associated with a higher rate of comorbidities,
between fewer exacerbations and inhaler satisfaction.136 functional disability, cognitive impairment, anaemia, lower al-
Mannino et al137 evaluated the effects of GOLD-adherent bumin and white blood cell levels, higher N-terminal pro-B-
prescribed treatment on symptoms, exacerbations and health- type natriuretic peptide and oral corticosteroids taken before
care resources utilisation by accessing data from electronic admission. They found a higher prevalence of cognitive impair-
health records. Their conclusion suggests that only ~36% ment in patients with AECOPD. In this study, the mortality rate
of COPD patients are prescribed medication accordingly of elderly patients during exacerbations was nearly 20%.143
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192    HOGEA et al.

FIGURE 1 Potential factors for COPD exacerbation

12 | H Y P OX IA A N D P = 0.0005) and used long-term oxygen therapy (41.5%

H Y P E RCA P N IA vs30.5%, P = 0.02). Also COPD patients with polyphar-
macy have often associated coronary artery disease, heart
Matkovic et al showed, in a prospective observational study, failure and a lower FEV 1% value. The treatment should be
that hypercapnia (P < 0.001) and hypoxemia (P = 0.008) in reviewed in these patients and, where possible, the number
patients admitted for AECOPD, were appreciated as inde- of drugs should be reduced in order to increase adherence
pendent predictors of poor outcome. Moreover, patients with to treatment and reduce the possibility of adverse effects
COPD and adverse outcomes more frequently used oxygen at and drug interactions.145
home (P = 0.042), had a lower PaO2/FiO2 (P = 0.006) and a
higher PaCO2 (P < 0.001), had lower pH (P < 0.001), a lower
FEV1 (P = 0.004), higher GOLD stage (P = 0.049) and had 14 | CONCLUSIONS
more exacerbations in the previous year (P = 0.004). Also
they evidenced that hypercapnia was the strongest prognostic The COPD exacerbations have many causes and these events
factor for an AECOPD, with a risk of 54%. These patients are a major cause of morbidity and mortality. Some of the
had a 9-fold higher risk of adverse outcome than patients risk factors and triggers of COPD exacerbations cause se-
with normocapnia (P < 0.001).144 vere exacerbations while others cause mild exacerbations.
Comorbidities such as CVD, bronchiectasis, GERD, mental
disorders and OSAS are prevalent in patients with COPD.
13 | P O LY P HA R MAC Y The comorbidities were associated with an increased risk of
AECOPD. AECOPD accelerate the functional decline, have
Some studies evidenced that polypharmacy is fre- a negative impact on quality of life and decrease survival.
quent among the patients hospitalised for AECOPD. It is important for physicians to identify patients at higher
Polypharmacy was defined as the chronic use of five or risk of exacerbation and try to prevent them. In these patients
more drugs, for more than 3 months prior the admission, the exacerbation of COPD can be prevented by immunisation
while excessive polypharmacy as the use of 10 or more and intensification of treatment.
medications. They observed that patients with polyphar- We tried to classify the risk factors according to the
macy were more frequently ex-smokers (75.4% vs 68.4%, severity of the exacerbations (Figure 1).
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HOGEA et al.    193

CONFLICT OF INTEREST 10. Kuwal A. A prospective study of bacteriological etiology in hospi-

The authors declare that they have no conflicts of interest talized acute exacerbation of COPD patients: relationship with lung
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with the contents of the article.
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Selected the articles included in the review and wrote the 12. Dy R, Sethi S. The lung microbiome and exacerbations of COPD.
draft: Hogea Vol. 22. Curr Opin Pulm Med. 2016;196-202.
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ORCID 17. Huang YJ, Boushey HA. The sputum microbiome in chronic ob-
Stanca-Patricia Hogea https://orcid. structive pulmonary disease exacerbations. Ann Am Thorac Soc.
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Ariadna Petronela Fildan https://orcid. 18. Casanova C, Soler-Cataluña JJ, Simonet P, et al. Guía española
org/0000-0002-5899-4904 de la enfermedad pulmonar obstructiva crónica (GesEPOC) 2017.
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