toxics

Article
Impact of Acute Exacerbation and Its Phenotypes on the
Clinical Outcomes of Chronic Obstructive Pulmonary Disease
in Hospitalized Patients: A Cross-Sectional Study
Mohammed Kaleem Ullah 1,2 , Ashwaghosha Parthasarathi 3,4 , Jayaraj Biligere Siddaiah 5 , Prashant Vishwanath 1 ,
Swapna Upadhyay 6 , Koustav Ganguly 6, *,† and Padukudru Anand Mahesh 5, *,†

1 Centre for Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry,
JSS Medical College, JSSAHER, Mysore 570015, Karnataka, India
2 Global Infectious Diseases Fellow, Division of Infectious Disease and Vaccinology, School of Public Health,
University of California, Berkeley, CA 94720, USA
3 Allergy, Asthma, and Chest Centre, Krishnamurthypuram, Mysore 570004, Karnataka, India
4 RUTGERS Centre for Pharmacoepidemiology and Treatment Science, New Brunswick, NJ 08901-1293, USA
5 Department of Respiratory Medicine, JSS Medical College, JSSAHER, Mysore 570015, Karnataka, India
6 Unit of Integrative Toxicology, Institute of Environmental Medicine (IMM), Karolinska Institutet,
17177 Stockholm, Sweden
* Correspondence: [email protected] (K.G.); [email protected] (P.A.M.)
† These authors contributed equally to this work.

Abstract: Acute exacerbations of COPD (AECOPD) are clinically significant events having thera-
peutic and prognostic consequences. However, there is a lot of variation in its clinical manifesta-
tions described by phenotypes. The phenotypes of AECOPD were categorized in this study based
Citation: Kaleem Ullah, M.;
on pathology and exposure. In our cross-sectional study, conducted between 1 January 2016 to
Parthasarathi, A.; Biligere Siddaiah, J.;
31 December 2020, the patients were categorized into six groups based on pathology: non-bacterial
Vishwanath, P.; Upadhyay, S.;
and non-eosinophilic; bacterial; eosinophilic; bacterial infection with eosinophilia; pneumonia; and
Ganguly, K.; Anand Mahesh, P.
bronchiectasis. Further, four groups were classified based on exposure to tobacco smoke (TS), biomass
Impact of Acute Exacerbation and Its
Phenotypes on the Clinical Outcomes
smoke (BMS), both, or no exposure. Cox proportional-hazards regression analyses were performed
of Chronic Obstructive Pulmonary to assess hazard ratios, and Kaplan–Meier analysis was performed to assess survival, which was
Disease in Hospitalized Patients: A then compared using the log-rank test. The odds ratio (OR) and independent predictors of ward
Cross-Sectional Study. Toxics 2022, 10, admission type and length of hospital stay were assessed using binomial logistic regression analyses.
667. https://doi.org/10.3390/ Of the 2236 subjects, 2194 were selected. The median age of the cohort was 67.0 (60.0 to 74.0) and
toxics10110667 75.2% were males. Mortality rates were higher in females than in males (6.2% vs. 2.3%). AECOPD-B
Academic Editor: Peter Franklin
(bacterial infection) subjects [HR 95% CI 6.42 (3.06–13.46)], followed by AECOPD-P (pneumonia)
subjects [HR (95% CI: 4.33 (2.01–9.30)], were at higher mortality risk and had a more extended hospital
Received: 29 September 2022 stay (6.0 (4.0 to 9.5) days; 6.0 (4.0 to 10.0). Subjects with TS and BMS-AECOPD [HR 95% CI 7.24
Accepted: 2 November 2022
(1.53–34.29)], followed by BMS-AECOPD [HR 95% CI 5.28 (2.46–11.35)], had higher mortality risk.
Published: 6 November 2022
Different phenotypes have different impacts on AECOPD clinical outcomes. A better understanding
Publisher’s Note: MDPI stays neutral of AECOPD phenotypes could contribute to developing an algorithm for the precise management of
with regard to jurisdictional claims in different phenotypes.
published maps and institutional affil-
iations. Keywords: COPD; acute exacerbation; phenotype; AECOPD; biomass; tobacco; mortality

Copyright: © 2022 by the authors.

1. Introduction
Licensee MDPI, Basel, Switzerland.
This article is an open access article Chronic obstructive pulmonary disease (COPD) is a preventable and treatable condi-
distributed under the terms and tion characterized by non-reversible airflow restriction responsible for significant morbidity,
conditions of the Creative Commons mortality, and healthcare expenditure globally [1,2]. In 2017, there were 545 million chronic
Attribution (CC BY) license (https:// respiratory disorders, of which COPD accounted for roughly 50%, with a global prevalence
creativecommons.org/licenses/by/ between 9% to 13% [3–5]. Sixty-five million individuals worldwide have moderate-to-
4.0/). severe COPD, and it is the third most common cause of death [6]. More than 3.23 million

Toxics 2022, 10, 667. https://doi.org/10.3390/toxics10110667 https://www.mdpi.com/journal/toxics

Toxics 2022, 10, 667 2 of 19

individuals died from COPD in 2019 [7], with low- and middle-income countries (LMICs)
suffering 80% of these fatalities [8,9]. Latin America, Sub-Saharan Africa, India, China, and
South-East Asia have the highest COPD mortality rates [10]. COPD is the second major
cause of non-communicable disease (NCD)-related fatalities in India, which accounts for
18% of the overall global population with COPD [11,12].
Acute exacerbations of COPD (AECOPD) are characterized by an acute aggravation
of the underlying chronic inflammation of the airways. They are associated with disease
progression, bacterial or viral infections, and exposure to environmental irritants [13].
AECOPD is distinguished by significant airflow obstruction that causes increased labor
of breathing and altered gas exchange [14]. Even one exacerbation can result in dete-
riorating lung function, eventually linked to poor prognosis, prolonged recovery, and
lower quality of life [15–17]. Lowering the likelihood of future exacerbations is one of
the critical objectives of COPD therapy, and clinicians accomplish this by using efficient
diagnosis and management strategies. However, the treatment of AECOPD includes var-
ious constraints and unknowns that vary depending on each patient’s pathobiological
heterogeneity and clinical presentation. Significant heterogeneity in the clinical presen-
tation, risk factors, exposures, and clinical outcomes are present among patients with
AECOPD [18,19]. Phenotype refers to the observable combination of disease attributes
that describe differences among patients. Several phenotypes of AECOPD have been
described previously. These phenotypes include AECOPD-Eosinophilia [20–26], AECOPD-
Bacterial [27–29], AECOPD-Pneumonia [30–38], and AECOPD-Bronchiectasis [39–41]. The
results of the MULTI-PHACET study indicate that most patients might have more than one
etiology contributing to AECOPD [42]. The etiology, inflammatory biomarkers, clinical
presentation, comorbidity, frequency of exacerbations, and other factors have been used to
categorize the phenotypes of AECOPD [43].
The two primary environmental risk factors for chronic obstructive pulmonary disease
(COPD) worldwide are cigarette smoking and biomass smoke [44]. Tobacco cigarettes are
highly processed with numerous inorganic toxic compounds, and biomass smoke is generated
from unprocessed organic matter [45]. A systematic review observed that COPD deaths
are associated with indoor pollution, and women are affected more than men due to higher
rates of exposure to indoor pollution [46]. Biomass smoke exposure in women leads to
the development of COPD, as seen in tobacco smokers, with decreased life expectancy and
increased mortality [47] but the two causes differ in the pathophysiological changes made
to the lungs due to the difference in chemical compositions between tobacco and biomass.
Females with biomass-exposed COPD are associated with more air-trapping, anthracosis, and
pulmonary fibrosis, and less emphysema, compared to tobacco-smoking COPD [48].
Most of these studies were performed in developed countries such as those in Europe
and North America [49]. There is a need to understand the various AECOPD phenotypes
in LMIC countries and their associated clinical outcomes such as mortality, need for ICU
admission, and length of hospital stay. It is equally essential to understand gender-based
differences in AECOPD outcomes and the effect of different types of exposure, such as
tobacco smoking and biomass fuel exposure, on AECOPD phenotypes and outcomes. This
study aimed to assess differences in clinically significant outcomes such as mortality, need
for ICU admission, and length of hospital stay between various AECOPD phenotypes
grouped according to the pathology or risk factors such as tobacco smoking and biomass
smoke exposure.

2. Materials and Methods

2.1. Cohort Description
This cross-sectional study was conducted in a tertiary care university teaching
hospital—JSS Medical College and Hospital, Mysore, India—by reviewing the subjects’
hospital records. The eligible subjects among the patients admitted between 1 January 2016
to 31 December 2020 were identified by the ICD-10 (International Classification of Diseases,
tenth edition) codes J44.1 and J44.9. A total of 2194 AECOPD subjects were included in
Toxics 2022, 10, 667 3 of 19

the study, constituting the Mysuru COPD (MYCO) Cohort. During the study period, age,
gender, comorbidities, length of hospital stay, admission to ward or ICU, outcome (sur-
vived/expired), and hematological investigations (neutrophils, lymphocytes, eosinophils,
monocytes, basophils, RBC count, and platelet count) were documented and recorded
from the hospital records. NLR (Absolute neutrophil count/Absolute lymphocyte count)
and Charlson’s comorbidity score were calculated. Any additional secondary diagnoses
were defined according to the ICD-10 coding system. Subjects’ demographic and clinical
characteristics are presented in Table 1 based on pathology and Table 2 based on exposure.

Table 1. Clinical characteristics of AECOPD phenotypes categorized based on pathology.

Total AECOPD-NBE AECOPD-B AECOPD-E AECOPD-BE AECOPD-P AECOPD-BC

(N = 2194) (N = 1025) (N = 251) (N = 388) (N = 53) (N = 309) (N = 168) p-Value

Age in years Median 67.0 (60.0 to 67.0 (60.0 to 66.0 (60.0 to 66.0 (59.0 to 70.0 (59.0 to 67.0 (60 to 0.016 *
65.0 (56 to 71.0)
(IQR) 74.0) 74.0) 74.5) 74.0) 75.0) 75.0)
Male (n,
Gender 1649 (75.2) 805 (78.5) 189 (75.3) 279 (71.9) 40 (75.5) 230 (74.4) 106 (63.1)
%) <0.001 †
Female (n,
545 (24.8) 220 (21.5) 62 (24.7) 109 (28.1) 13 (24.5) 79 (25.6) 62 (36.9)
%)
Median 5.0 (3.0 to 6.0 (4.0 to 4.0 (3.0 to 6.0 (4.0 to 6.0 (4.0 to <0.001 *
LOS in days 5.0 (3.0 to 7.0) 5.0 (4.0 to 8.0)
(IQR) 8.0) 9.5) 6.0) 9.0) 10.0)
Ward (n,
Admission to 1794 (81.8) 926 (90.3) 123 (49.0) 380 (97.9) 37 (69.8) 199 (64.4) 129 (76.8)
Ward/ICU
%) <0.001 †
ICU (n, %) 400 (18.2) 99 (9.7) 128 (51.0) 8 (2.1) 16 (30.2) 110 (35.6) 39 (23.2)
Alive (n,
Hospital 2122 (96.7) 1015 (99) 223 (88.8) 388 (100) 50 (94.3) 285 (92.2) 161 (95.8)
outcome
%) <0.001 †
Dead (n,
72 (3.3) 10 (1.0) 28 (11.2) 0 (0) 3 (5.7) 24 (7.8) 7 (4.2)
%)
Bacterial
infection
Yes (n, %) 432 (19.7) 0 (0) 251 (100) 0 (0) 53 (100) 85 (27.5) 43 (25.6) <0.001 †
Alcohol
consumption
Yes (n, %) 310 (14.1) 170 (16.6) 21 (8.4) 52 (13.4) 2 (3.8) 50 (16.2) 15 (8.9) 0.001 †
NTS and
NBMS- Yes (n, %) 637 (29.0) 295 (28.8) 75 (29.9) 128 (33.0) 17 (32.1) 76 (24.6) 46 (27.4)
AECOPD
TS-AECOPD Yes (n, %) 1100 (50.1) 560 (54.6) 114 (45.4) 179 (46.1) 21 (39.6) 165 (53.4) 61 (36.3) <0.001 †
BMS-AECOPD Yes (n, %) 425 (19.4) 164 (16.0) 54 (21.5) 77 (19.8) 13 (24.5) 66 (21.4) 51 (30.4)
TS and
Yes (n, %) 32 (1.5) 6 (0.6) 8 (3.2) 4 (1.0) 2 (3.8) 2 (0.6) 10 (6.0)
BMS-AECOPD
CCI Median 4.0 (3.0 to 4.0 (3.0 to 3.0 (2.0 to 4.0 (3.0 to 4.0 (3.0 to <0.001 *
(IQR) 5.0) 4.0 (3.0 to 5.0) 5.0) 4.0) 5.0) 5.0) 3.0 (2.0 to 4.0)
Comorbidities
Diabetes
mellitus
Yes (n, %) 522 (23.8) 249 (24.3) 60 (23.9) 88 (22.7) 14 (26.4) 77 (24.9) 34 (20.2) 0.850 †
Heart diseases Yes (n, %) 327 (14.9) 162 (15.8) 37 (14.7) 53 (13.7) 9 (17.0) 45 (14.6) 21 (12.5) 0.834 †
Renal diseases Yes (n, %) 186 (8.5) 86 (8.4) 26 (10.4) 20 (5.2) 5 (9.4) 41 (13.3) 8 (4.8) 0.002 †
Liver diseases Yes (n, %) 56 (2.6) 29 (2.8) 13 (5.2) 5 (1.3) 1 (1.9) 7 (2.3) 1 (0.6) 0.028 †
Cor pulmonale Yes (n, %) 452 (20.6) 217 (21.2) 62 (24.7) 57 (14.7) 5 (9.4) 63 (20.4) 48 (28.6) <0.001 †
Hypertension Yes (n, %) 758 (34.5) 362 (35.3) 88 (35.1) 140 (36.1) 23 (43.4) 100 (32.4) 45 (26.8) 0.176 †
Obesity Yes (n, %) 129 (5.9) 61 (6.0) 14 (5.6) 33 (8.5) 7 (13.2) 12 (3.9) 2 (1.2) 0.002 †
OSA Yes (n, %) 137 (6.2) 64 (6.2) 12 (4.8) 37 (9.5) 7 (13.2) 16 (5.2) 1 (0.6) <0.001 †
PAH Yes (n, %) 383 (17.5) 163 (15.9) 49 (19.5) 65 (16.8) 17 (32.1) 46 (14.9) 43 (25.6) 0.001 †
Sepsis Yes (n, %) 94 (4.3) 19 (1.9) 15 (6.0) 1 (0.3) 0 (0) 53 (17.2) 6 (3.6) <0.001 †
T1RF Yes (n, %) 80 (3.6) 35 (3.4) 12 (4.8) 13 (3.4) 1 (1.9) 15 (4.9) 4 (2.4) 0.595 †
T2RF Yes (n, %) 371 (16.9) 166 (16.2) 61 (24.3) 30 (7.7) 14 (26.4) 69 (22.3) 31 (18.5) <0.001 †
Lymphocytes Median 13.5 (7.3 to 12.6 (6.7 to 10.0 (5.1 to 20.4 (14.2 to 18.1 (11.0 to 9.6 (5.05 to 14.5 (8.15 to <0.001 *
% (IQR) 21) 19.3) 16.5) 27.5) 25.7) 16.4) 19.8)
Median 1.05 (0.2 to 0.2 (0.0 to 4.90 (3.9 to 4.40 (3.8 to 0.5 (0.1 to <0.001 *
Eosinophils % 0.5 (0.1 to 1.3) 0.9 (0.2 to 3.0)
(IQR) 3.3) 1.2) 6.73) 5.50) 1.85)
Monocytes % Median 4.5 (3.1 to 4.3 (2.8 to 5.0 (3.9 to 4.35 (3.10 to 3.95 (2.4 to <0.001 *
4.3 (3.0 to 5.9) 4.7 (2.85 to 6.0)
(IQR) 6.0) 5.8) 6.2) 5.93) 5.45)
Median 0.3 (0.2 to 0.3 (0.2 to 0.4 (0.3 to 0.4 (0.2 to 0.3 (0.2 to <0.001 *
Basophils % 0.3 (0.2 to 0.5) 0.3 (0.2 to 0.5)
(IQR) 0.5) 0.5) 0.7) 0.6) 0.5)
RBC count
(mil- Median 4.63 (4.16 to 4.68 (4.21 to 4.66 (4.28 to 4.59 (4.15 to 4.70 (4.35 to 4.46 (4.0 to 4.58 (4.09 to 0.002 *
lion/cumm) (IQR) 5.15) 5.2) 5.21) 5.06) 5.05) 4.97) 5.23)
Platelet count
Median 2.49 (1.94 to 2.51 (1.97 to 2.46 (1.83 to 2.5 (2.08 to 2.47 (2.03 to 2.43 (1.69 to 2.54 (1.97 to 0.483 *
(lakh
(IQR) 3.17) 3.27) 3.19) 3.03) 2.84) 3.11) 3.29)
cells/cumm)
NLR Median 5.9 (3.3 to 6.55 (3.8 to 8.50 (4.6 to 3.3 (2.2 to 4.05 (2.4 to 8.50 (4.7 to 5.40 (3.5 to <0.001 *
(IQR) 12.0) 13.3) 17.6) 5.30) 7.35) 17.8) 10.3)

* Kruskal–Wallis test. † Pearson Chi sq. test. LOS: Length of hospital stay, AECOPD: Acute exacerbation of
chronic obstructive pulmonary diseases, NBE: No bacterial infection and no eosinophilia, B: Bacterial infection,
E: Eosinophilia and no bacterial infections, BE: Bacterial infection with eosinophilia, P: Pneumonia, BC: Bronchiec-
tasis, NTS and NBMS: Non-tobacco smoke and non-biomass smoke, TS: Tobacco smoke, BMS: Biomass smoke,
TS and BMS: Tobacco smoke and biomass smoke, CCI: Charlson comorbidity index, OSA: Obstructive sleep
apnea, PAH: Pulmonary hypertension, T1RF: Type 1 respiratory failure, T2RF: Type 2 respiratory failure, NLR:
Neutrophil–lymphocytes ratio.
Toxics 2022, 10, 667 4 of 19

Table 2. Clinical characteristics of AECOPD phenotypes categorized based on exposure type.

NTS- and
TS- and
NBMS- TS-AECOPD BMS-AECOPD
BMS-AECOPD p-Value
AECOPD (N = 1100) (N = 425)
(N = 32)
(N = 637)
Age in years Median (IQR) 68 (61.0 to 75.0) 66 (60.0 to 73.0) 66 (58.0 to 74.0) 65 (61.5 to 68.3) <0.01 *
Male Yes (n, %) 498 (78.2) 1091 (99.2) 28 (6.6) 32 (100)
Female Yes (n, %) 139 (21.8) 9 (0.8) 397 (93.4) 0 (0) <0.01 †
LOS in days Median (IQR) 5.0 (3.0 to 8.0) 5.0 (3.0 to 7.0) 6.0 (4.0 to 8.0) 5.0 (3.0 to 7.0) 0.019 *
Ward Ward (n, %) 516 (81.0) 906 (82.4) 347 (81.6) 25 (78.1)
ICU ICU (n, %) 121 (19) 194 (17.6) 78 (18.4) 7 (21.9) 0.85 †
Alive Alive (n, %) 627 (98.4) 1070 (97.3) 395 (92.9) 30 (93.8)
Dead Dead (n, %) 10 (1.6) 30 (2.7) 30 (7.1) 2 (6.3) <0.01 †
CCI Median (IQR) 4.0 (3.0 to 5.0) 4.0 (3.0 to 5.0) 4.0 (3.0 to 5.0) 3.0 (3.0 to 4.0) <0.01 *
Bacterial
Yes (n, %) 131 (20.6) 198 (18.0) 92 (21.6) 11 (34.4) 0.05 †
infection
Alcohol
Yes (n, %) 19 (3.0) 283 (25.7) 1 (0.2) 7 (21.9) <0.01 †
consumption
Diabetes
Yes (n, %) 184 (28.9) 223 (20.3) 110 (25.9) 5 (15.6) <0.01 †
mellitus
Heart diseases Yes (n, %) 134 (21.0) 140 (12.7) 49 (11.5) 4 (12.5) <0.01 †
Renal diseases Yes (n, %) 74 (11.6) 87 (7.9) 25 (5.9) 0 (0) <0.01 †
Liver diseases Yes (n, %) 19 (3) 32 (2.9) 4 (0.9) 1 (3.1) 0.14 †
Cor pulmonale Yes (n, %) 141 (22.1) 180 (16.4) 122 (28.7) 9 (28.1) <0.01 †
Hypertension Yes (n, %) 268 (42.1) 293 (26.6) 189 (44.5) 8 (25.0) <0.01 †
Obesity Yes (n, %) 38 (6.0) 40 (3.6) 49 (11.5) 2 (6.3) <0.01 †
OSA Yes (n, %) 39 (6.1) 42 (3.8) 54 (12.7) 2 (6.3) <0.01 †
PAH Yes (n, %) 92 (14.4) 195 (17.7) 88 (20.7) 8 (25.0) 0.04 †
Sepsis Yes (n, %) 26 (4.1) 46 (4.2) 20 (4.7) 2 (6.3) 0.90 †
T1RF Yes (n, %) 16 (2.5) 47 (4.3) 17 (4.0) 0 (0) 0.18 †
T2RF Yes (n, %) 100 (15.7) 166 (15.1) 96 (22.6) 9 (28.1) <0.01 †
AECOPD-NBE Yes (n, %) 295 (46.3) 560 (50.9) 164 (38.6) 6 (18.8)
AECOPD-E Yes (n, %) 128 (20.1) 179 (16.3) 77 (18.1) 4 (12.5)
AECOPD-P Yes (n, %) 76 (11.9) 165 (15.0) 66 (15.5) 2 (6.3)
AECOPD-BC Yes (n, %) 46 (7.2) 61 (5.5) 51 (12.0) 10 (31.3) <0.01 †
AECOPD-B Yes (n, %) 75 (11.8) 114 (10.4) 54 (12.7) 8 (25.0)
AECOPD-BE Yes (n, %) 17 (2.7) 21 (1.9) 13 (3.1) 2 (6.3)
Lymphocytes % Median (IQR) 13.5 (7.45 to 22.1) 12.9 (6.8 to 20) 15.25 (9.6 to 22.1) 12.8 (6.6 to 23.9) <0.001 *
Eosinophils % Median (IQR) 1.3 (0.2 to 3.6) 0.85 (0.1 to 3.0) 1.3 (0.2 to 3.6) 2.4 (0.4 to 3.9) 0.001 *
Monocytes % Median (IQR) 4.6 (3.3 to 6.2) 4.5 (3.0 to 6.0) 4.2 (3.1 to 5.4) 5.2 (3.2 to 6.4) 0.068 *
Basophils % Median (IQR) 0.3 (0.2 to 0.5) 0.3 (0.2 to 0.5) 0.3 (0.2 to 0.5) 0.3 (0.2 to 0.5) 0.811 *
RBC count (mil-
Median (IQR) 4.5 (4.0 to 5.1) 4.7 (4.3 to 5.3) 4.46 (4.1 to 4.9) 4.83 (4.6 to 5.3) <0.001 *
lion/cumm)
Platelet count
(lakh Median (IQR) 2.47 (1.91 to 3.1) 2.46 (1.86 to 3.18) 2.65 (2.16 to 3.32) 2.090 (1.95 to 2.5) < 0.001 *
cells/cumm)
NLR Median (IQR) 5.90 (3.0 to 11.6) 6.10 (3.5 to 13.2) 5.15 (3.2 to 8.77) 6.10 (3.0 to 13.4) 0.002 *
†
* Kruskal–Wallis test. Pearson Chi sq. test. LOS: Length of hospital stay, AECOPD: Acute exacerbation of
chronic obstructive pulmonary diseases, NBE: No bacterial infection and no eosinophilia, B: Bacterial infection,
E: Eosinophilia and no bacterial infections, BE: Bacterial infection with eosinophilia, P: Pneumonia, BC: Bronchiec-
tasis, NTS and NBMS: Non-tobacco smoke and non-biomass smoke, TS: Tobacco smoke, BMS: Biomass smoke,
TS and BMS: Tobacco smoke and biomass smoke, CCI: Charlson comorbidity index, OSA: Obstructive sleep
apnea, PAH: Pulmonary hypertension, T1RF: Type 1 respiratory failure, T2RF: Type 2 respiratory failure, NLR:
Neutrophil–lymphocytes ratio.

2.2. Definitions
COPD is a common, preventable, treatable disease characterized by persistent res-
piratory symptoms and airflow limitation due to airway and/or alveolar abnormalities,
usually caused by significant exposure to noxious particles or gases and influenced by host
factors including abnormal lung development [2]. AECOPD is defined as acute worsening
Toxics 2022, 10, 667 5 of 19

of respiratory symptoms (such as increase in coughing, quantity of sputum, breathlessness,

or increase in purulence of sputum) that results in additional therapy [50]. Cor pulmonale,
pulmonary hypertension, and other additional diagnoses are defined according to the
ICD10 coding system. Charlson’s comorbidity index was calculated as a composite risk
of all associated comorbidities, where a higher score predicts a higher risk of mortality or
higher resource-use [51].
Bacterial infection was defined as the presence of positive sputum culture for pathogenic
bacteria. Eosinophilia was defined as the presence of 3% or more eosinophils in the dif-
ferential leukocyte count [52]. The presence of an ICD-10 code identified pneumonia and
bronchiectasis subjects.
Smokers are defined as adult smokers with a smoking history of >10 pack years.
The burning of various fuels, including wood, animal dung, and crop wastes, to produce
the energy required for heating and cooking in many houses worldwide results in the
production of biomass smoke [53]. Biomass exposure is defined as chronic exposure to
biomass smoke for at least ten years [54,55]. Non-tobacco smoke and non-biomass smoke
COPD might be due to causes other than smoking and biomass exposure, such as prolonged
exposure to dust due to dusty occupations such as agricultural farming, sericulture farming,
working in the cotton industry, chronic asthma, and post-TB sequelae.
The common reasons for hospitalization of AECOPD subjects in the general ward were
failed response to initial medical management, severe symptoms, serious comorbidities,
the onset of new physical signs, and acute respiratory failure (without using accessory
respiratory muscles). Common symptoms for admission to respiratory or medical ICU
are very severe symptoms, acute respiratory failure (with accessory respiratory muscle),
persistent or worsening hypoxemia and/or severe respiratory acidosis, need for non-
invasive or invasive mechanical ventilation, and hemodynamic instability [50].
The subjects were categorized based on pathology and exposure as below. Pathology
phenotypes (six groups):
1. AECOPD-Non-bacterial and non-eosinophilic (NBE) group, consisting of AECOPD
subjects who had no bacterial infection and no peripheral blood eosinophilia;
2. AECOPD-Bacterial (B) group, consisting of subjects who had bacterial AECOPD
without eosinophilia;
3. AECOPD-Eosinophilia (E) group, consisting of AECOPD subjects who had peripheral
blood eosinophilia and no bacterial infections;
4. AECOPD-Bacterial with eosinophilia (BE) group, consisting of subjects who had
bacterial AECOPD with peripheral blood eosinophilia;
5. AECOPD-Pneumonia (P) group, consisting of AECOPD subjects with pneumonia;
6. AECOPD-Bronchiectasis (BC) group, consisting of AECOPD subjects with bronchiectasis.
Exposure groups (four groups):
1. Non-tobacco smoke and non-biomass smoke (NTS and NBMS) AECOPD group,
consisting of AECOPD subjects who were non-smokers with no biomass exposure;
2. Tobacco smoke (TS) AECOPD group, consisting of AECOPD subjects who were
smokers;
3. Biomass smoke (BS) AECOPD group, consisting of AECOPD subjects who were
exposed to biomass smoke;
4. Tobacco smoke and biomass smoke (TS and BMS) AECOPD group, consisting of
AECOPD subjects who were smokers with biomass exposure.
The subjects eligible were identified by the ICD-10 codes J44.1 and J44.9. Male and
female subjects ≥ 40 years of age diagnosed with acute exacerbation of COPD were included
in the study. Subjects with relevant missing data were excluded from the study.

2.3. Statistical Analysis

Statistical analysis was performed employing Jamovi (v1.6, The Jamovi project, SYD,
AUS). Data were checked for normality of distribution using Shapiro–Wilk’s test. If they
Toxics 2022, 10, 667 6 of 19

were normally distributed, continuous variables were presented as mean ± standard

deviation. If not, they were presented as median with their interquartile range. Categorical
variables were presented as percentages. Statistical significance was assessed by the Chi-
square test for categorical variables and by the Kruskal–Wallis test for continuous variables
and expressed with medians and interquartile ranges (IQRs). Cox proportional-hazards
regression analyses were performed to assess univariate and multivariate hazard ratios.
The Kaplan–Meier method was used to draw survival curves, while the survival rates were
compared using the log-rank test. The odds ratio (OR) and independent predictors of type
of ward admission and length of hospital stay were assessed by binomial logistic regression
analyses. A two-tailed p-value of <0.05 was considered statistically significant.

3. Results
During the five-year study period, 2194 AECOPD patients met the inclusion criteria
and were categorized into six groups based on pathology; the most common group was the
AECOPD-NBE group (n = 1025, 46.7%), followed by the AECOPD-E group (n = 388, 17.7%),
AECOPD-P group (n = 309, 14.1%), AECOPD-B group (n = 251, 11.4%), AECOPD-BC group
(n = 168, 7.7%), and AECOPD-BE group (n = 53, 2.4%). Patients were further categorized
into four groups based on exposure; the most common group was TS-AECOPD (n = 1100,
50.1%), followed by NTS and NBMS-AECOPD (n = 637, 29%), BMS-AECOPD (n = 425,
19.4%), and TS and BMS-AECOPD (n = 32, 1.5%) (Figure 1). The median (IQR) age of the
subjects was 67.0 (60.0 to 74.0). Males accounted for 75.2% of the study subjects. Among
the common comorbidities documented, diabetes mellitus (23.8%) was the most common,
followed by heart disease (14.9%) and renal disease (8.5%), and when stratified based on
sex, females had higher rates of diabetes mellitus (30.6; p < 0.001) while males had higher
incidence of heart diseases (15.6%; p = 0.09) and renal diseases (3.2%; p = 0.007) (Table S1).
The AECOPD-BC group consisted of younger subjects [65 (56 to 71)] compared to
the other groups (p < 0.016). The AECOPD-BC group had a higher proportion of females
(36.9%) compared to the other groups (p < 0.001). A longer duration of hospital stay
(p < 0.001) was observed in AECOPD subjects with bacterial infection (AECOPD-B group
and AECOPD-BE group) and pneumonia (AECOPD-P group). The highest incidence
of ICU admissions were observed in the AECOPD-B group (51%), and the lowest were
observed in the AECOPD-E group (2.1%) (p < 0.001). Higher mortality was observed in
the AECOPD-B group (11.2%), and no mortality was observed in the AECOPD-E group
(0%) (p < 0.001). A total of 54.6% of cases observed with AECOPD-NBE were smokers,
followed by AECOPD-P (53.4%); AECOPD-BC had higher incidence of BMS-AECOPD
(30.4%), followed by AECOPD-BE (24.5%). In the case of TS and BMS-AECOPD, it was
highest in AECOPD-BC (6%) followed by AECOPD-BE (3.8%) (p < 0.001) (Table 1).
Overall, mortality was higher in females when compared to males (6.2% vs. 2.3%,
respectively; p < 0.001) (Table S1), and in all the different phenotypes, higher mortality in fe-
males was observed than in males. This was such for cases of AECOPD-NBE (2.7% vs. 0.5%,
respectively; p = 0.003), AECOPD-P (11.4% vs. 6.5%, respectively; p = 0.163), AECOPD-BC
(6.5% vs. 2.8%, respectively; p = 0.257), AECOPD-B (21% vs. 7.9%, respectively; p = 0.005),
and AECOPD-BE (15.4% vs. 2.5%, respectively; p = 0.081) (Table S2). A total of 27.5% of
AECOPD-P patients had bacterial pneumonia, and the remaining cases were non-bacterial
pneumonia. Of the AECOPD-BC group, 25.6% of patients had bacterial infections and the
remaining patients had non-bacterial bronchiectasis. A higher NLR ratio (p < 0.001) was ob-
served in the AECOPD-P and AECOPD-B groups, and the lowest NLR ratio was observed
in the AECOPD-E group. The AECOPD-E group had significantly higher lymphocyte [20.4
(14.2 to 27.5); p < 0.001], eosinophil [4.90 (3.9 to 6.73); p < 0.001], monocyte [5.0 (3.9 to 6.2);
p < 0.001], and basophil [0.4 (0.3 to 0.7); p < 0.001] counts than any other phenotypes. The
AECOPD-BE group had a significantly higher RBC count [4.70 (4.35 to 5.05); p = 0.002].
The AECOPD-B [8.50 (4.6 to 17.6); p < 0.001] and AECOPD-P [8.50 (4.7 to 17.8); p < 0.001]
groups had significantly higher neutrophil–lymphocyte ratios. The AECOPD-P group
had significantly lower lymphocyte [9.6 (5.05 to 16.4); p < 0.001], monocyte [3.95 (2.4 to
Toxics 2022, 10, 667 7 of 19

5.45); p < 0.001], and RBC [4.46 (4.0 to 4.97); p = 0.002] counts. The AECOPD-B group had
Toxics 2022, 10, x 7 of 24
significantly lower eosinophils [0.2 (0.0 to 1.2); p < 0.001]. The AECOPD-E group had a
significantly lower neutrophil–lymphocyte ratio [3.3 (2.2 to 5.30); p < 0.001] (Table 1).

Figure 1. Flowchart of the study describing the categorization of AECOPD phenotypes based on
Figure 1. Flowchart
exposure of the study
and pathology describing
and their mortality.the categorization
Red: Expired, Green:ofAlive,
AECOPDAECOPD:phenotypes based on
Acute exacerbation of expo-
chronic obstructive pulmonary diseases, NBE: No bacterial infection and no eosinophilia,
sure and pathology and their mortality. Red: Expired, Green: Alive, AECOPD: Acute exacerbation of B: Bacterial infection,
E: Eosinophilia and no bacterial infections, BE: Bacterial infection with eosinophilia, P: Pneumonia, BC: Bron-
chronic obstructive pulmonary diseases, NBE: No bacterial infection and no eosinophilia, B: Bacterial
chiectasis, NTS and NBMS: Non-tobacco smoke and non-biomass smoke AECOPD, TS: Tobacco smoke, BMS:
infection,
BiomassE:smoke,
Eosinophilia andTobacco
TS and BMS: no bacterial
smoke andinfections, BE: Bacterial infection with eosinophilia, P: Pneu-
biomass smoke.
monia, BC: Bronchiectasis, NTS and NBMS: Non-tobacco smoke and non-biomass smoke AECOPD,
TS: TobaccoThesmoke,
AECOPD-BC group consisted
BMS: Biomass smoke, TSofand younger subjectssmoke
BMS: Tobacco [65 (56and
to 71)] compared
biomass smoke.to
the other groups (p < 0.016). The AECOPD-BC group had a higher proportion of females
(36.9%)
The TS compared to the other groups
and BMS-AECOPD group (p consisted
< 0.001). A of longer duration
younger of hospital
subjects stay (p
[65 (61.5 to<68.3)]
0.001) was observed in AECOPD subjects with bacterial
compared to other groups (p < 0.01). The BMS-AECOPD group had a higher proportion infection (AECOPD-B group
and AECOPD-BE
of females group) and to
(93.4%) compared pneumonia
other groups (AECOPD-P group).
(p < 0.01). A The highest
longer incidence
duration of
of hospital
ICU admissions were observed in the AECOPD-B group (51%), and the lowest were ob-
stay (p = 0.019) was observed in the BMS-AECOPD group. The TS-AECOPD group had
served in the AECOPD-E group (2.1%) (p < 0.001). Higher mortality was observed in the
a significantly higher neutrophil–lymphocyte ratio [6.10 (3.5 to 13.2); p < 0.002], while
AECOPD-B group (11.2%), and no mortality was observed in the AECOPD-E group
BMS-AECOPD
(0%) (p < 0.001). hadA higher
total of lymphocyte
54.6% of cases[15.25 (9.6 with
observed to 22.1); p < 0.001] were
AECOPD-NBE and platelet
smokers,count
[2.65 (2.16 to 3.32); p < 0.001]; TS and BMS-AECOPD
followed by AECOPD-P (53.4%); AECOPD-BC had higher incidence of BMS-AECOPD had higher eosinophil [2.4 (0.4
to 3.9); p < followed
(30.4%), 0.001] and RBC count [4.83
by AECOPD-BE (24.5%). casepof
(4.6Intothe5.3); < TS
0.001], and a higher neutrophil–
and BMS-AECOPD, it was
lymphocyte
highest in ratio [6.10 (3.0
AECOPD-BC to 13.4);
(6%) followed p <by 0.002].
AECOPD-BEThe highest
(3.8%)mortality
(p < 0.001) was
(Table observed
1). in the
BMS-AECOPD Overall, mortality
group (7.1%)was higher
and the in females when compared
lowest mortality in thetoNTSmalesand (6.2% vs. 2.3%,
NBMS-AECOPD
respectively;
group < 0.001)
(1.6) (p <p0.01) (Table
(Table 2). S1),
When andthein all the of
type different
exposure phenotypes, higher based
was stratified mortality
on ingender,
we females
observed was observed than
a significant in males.
difference This wasmale
between suchandfor cases
female of mortality
AECOPD-NBE in NTS(2.7%andvs.NBMS-
AECOPD (1.0% vs. 3.6%, respectively; p = 0.030) and BMS-AECOPD (3.6% vs. 7.3%,
respectively; p = 0.456). Still, in TS-AECOPD, higher mortality was observed in males
 Toxics 2022, 10, 667 8 of 19

(2.7% vs. 0%, respectively; p = 0.614) and the TS and BMS-AECOPD group had only male
patients, with a 6.3% mortality rate (Table S3).
A significant difference between the six groups was observed following Kaplan–Meier
analysis using the log-rank test (p < 0.0001) (Figure 2), which showed that the AECOPD-
B group had a significantly higher risk of mortality compared to the other groups. A
pairwise comparison was also performed for each group (Table 3). We observed that
intergroup comparisons for survival among conditions associated with bacterial infections
such as AECOPD-B, AECOPD-BE, AECOPD-P, and AECOPD-BC were not statistically
significant. Intergroup comparisons for survival between conditions related to bacterial
Toxics 2022, 10, x infections (AECOPD-B, AECOPD-BE, AECOPD-P, and AECOPD-BC) and those without 9 of 24
bacterial infections (AECOPD-E and AECOPD-NBE) were statistically significant, except
for AECOPD-BE with AECOPD-NBE.

Figure Kaplan–Meier
2. 2.
Figure Kaplan–Meier survival
survivalcurve
curvefor
forphenotypes
phenotypesbased
based onon pathology.
pathology. AECOPD:
AECOPD: AcuteAcute exac-
erbation of chronic obstructive pulmonary diseases, NBE: No bacterial infection
exacerbation of chronic obstructive pulmonary diseases, NBE: No bacterial infection and and nonoeosino-
philia,
eosinophilia, B: Bacterial infection, E: Eosinophilia and no bacterial infections, BE: bacterial infection with
B: Bacterial infection, E: Eosinophilia and no bacterial infections, BE: bacterial infection
eosinophilia, P: Pneumonia,
with eosinophilia, and BC:
P: Pneumonia, and Bronchiectasis.
BC: Bronchiectasis.
A significant difference between the four groups was observed following Kaplan–
Table 3. Pairwise comparisons for AECOPD phenotypes categorized based on pathology.
Meier analysis using the log-rank test (p < 0.0001), which showed that the BMS-AECOPD
group had aLevels
significantly higher risk of mortality Levels
compared to the other groups p-Value
(Figure 3).
A pairwise comparison was also performed for each group (Table 4). Three intergroup
AECOPD-E AECOPD-NBE 0.529
comparisons for survival were significant: BMS-AECOPD vs. NTS and NBMS-AECOPD,
AECOPD-P AECOPD-NBE
BMS-AECOPD vs. TS-AECOPD, and TS and BMS-AECOPD vs. NTS and NBMS-AECOPD.
<0.001
AECOPD-P AECOPD-E <0.001
AECOPD-BC AECOPD-NBE 0.146
AECOPD-BC AECOPD-E 0.008
AECOPD-BC AECOPD-P 1.000
AECOPD-B AECOPD-NBE <0.001
AECOPD-B AECOPD-E <0.001
AECOPD-B AECOPD-P 1.000
AECOPD-B AECOPD-BC 0.389
AECOPD-BE AECOPD-NBE 0.356
 Toxics 2022, 10, 667 9 of 19

Table 3. Pairwise comparisons for AECOPD phenotypes categorized based on pathology.

Levels Levels p-Value

AECOPD-E AECOPD-NBE 0.529
AECOPD-P AECOPD-NBE <0.001
AECOPD-P AECOPD-E <0.001
AECOPD-BC AECOPD-NBE 0.146
AECOPD-BC AECOPD-E 0.008
AECOPD-BC AECOPD-P 1.000
Toxics 2022, 10, x AECOPD-B AECOPD-NBE <0.001 10 of 2
AECOPD-B AECOPD-E <0.001
AECOPD-B AECOPD-P 1.000
AECOPD-B AECOPD-BC 0.389
3). A pairwise comparison was also
AECOPD-BE performed for each group0.356
AECOPD-NBE (Table 4). Three inter
AECOPD-BE AECOPD-E 0.090
group comparisons
AECOPD-BE for survival were significant:
AECOPD-P BMS-AECOPD vs. NTS and NBMS
1.000
AECOPD, BMS-AECOPD vs. TS-AECOPD,
AECOPD-BE AECOPD-BC and TS and BMS-AECOPD
1.000 vs. NTS and
NBMS-AECOPD.
AECOPD-BE AECOPD-B 1.000
Note: p-value adjusted using Holm method. AECOPD: Acute exacerbation of chronic obstructive pulmonary
diseases, NBE: No bacterial infection and no eosinophilia, B: Bacterial infection, E: Eosinophilia and no bacterial
infections, BE: Bacterial infection with eosinophilia, P: Pneumonia, and BC: Bronchiectasis.

Figure 3. Kaplan–Meier survival curve for phenotypes based on exposure. Definition of abbreviations:
AECOPD: Acute exacerbation of chronic obstructive pulmonary diseases, NTS and NBMS: Non-
3. Kaplan–Meier
Figure smoke
tobacco survival
and non-biomass curve
smoke, for phenotypes
TS: Tobacco based
smoke, BMS: on exposure.
Biomass smoke, and Definition of abbrevia
TS and BMS:
tions: AECOPD: Acute exacerbation
Tobacco smoke and biomass smoke. of chronic obstructive pulmonary diseases, NTS and NBMS
Non-tobacco smoke and non-biomass smoke, TS: Tobacco smoke, BMS: Biomass smoke, and TS
and BMS: Tobacco smoke and biomass smoke.

Table 4. Pairwise comparisons of AECOPD phenotypes categorized based on exposure type.

Levels Levels p-Value

TS-AECOPD NTS and NBMS-AECOPD 0.095
BMS-AECOPD NTS and NBMS-AECOPD <0.001
Toxics 2022, 10, 667 10 of 19

Table 4. Pairwise comparisons of AECOPD phenotypes categorized based on exposure type.

Levels Levels p-Value

TS-AECOPD NTS and NBMS-AECOPD 0.095
BMS-AECOPD NTS and NBMS-AECOPD <0.001
BMS-AECOPD TS-AECOPD 0.009
TS and BMS-AECOPD NTS and NBMS-AECOPD 0.034
TS and BMS-AECOPD TS-AECOPD 0.210
TS and BMS-AECOPD BMS-AECOPD 0.838
Note. p-value adjusted using the Holm method. AECOPD: Acute exacerbation of chronic obstructive pulmonary
diseases, NTS and NBMS: Non-tobacco smoke and non-biomass smoke, TS: Tobacco smoke, BMS: Biomass smoke,
and TS and BMS: Tobacco smoke and biomass smoke.

Two models were considered to evaluate factors with independent association to

mortality. Model 1 assessed exposures and model 2 considered only phenotypes based on
pathology (Table 5). Univariate Cox proportional-hazard regression analysis for survival
in model 1 showed that females, those older than 60, those with type 2 respiratory failure,
patients with sepsis, and the AECOPD-B, AECOPD-P, and AECOPD-BC groups were asso-
ciated with poor survival. On multivariate Cox proportional-hazard regression analysis,
females [Hazards ratio (HR) (95% Confidence Interval (CI): 3.05 (1.83–5.09)], type 2 respira-
tory failure [HR (95% CI: 1.74 (1.04–2.91)], sepsis [HR (95% CI: 3.13 (1.72–5.71)], AECOPD-B
group membership [HR 95% CI 6.42 (3.06–13.46,)], AECOPD-BE group membership [HR
(95% CI: 3.84 (1.04–14.20)], AECOPD-P group membership [HR (95% CI: 4.33 (2.01–9.30)],
and AECOPD-BC group membership [HR (95% CI: 2.72 (1.00–7.38)] were found to be
independently associated with poor survival (Model 1: Table 5).

Table 5. Hazard ratio (H.R.) reflecting mortality risk was calculated by multivariate Cox
regression analysis.

Model 1: Pathology Model 2: Exposure

HR HR HR HR
(Univariable) (Multivariable) (Univariable) (Multivariable)
Sex Male Reference Reference - -
Female 2.47 (1.55–3.93) *** 3.05 (1.83–5.09) *** - -
Age Mean (SD) 1.02 (1.00–1.05) * 1.03 (1.00–1.06) 1.02 (1.00–1.05) * 1.03 (1.00–1.06)
Cor pulmonale Yes 1.37 (0.83–2.26) 0.76 (0.44–1.32) 1.37 (0.83–2.26) 0.91 (0.54–1.54)
T1RF Yes 0.83 (0.20–3.40) 0.88 (0.21–3.66) 0.83 (0.20–3.40) 1.01 (0.24–4.21)
T2RF Yes 2.21 (1.37–3.56) *** 1.74 (1.04–2.91) * 2.21 (1.37–3.56) *** 1.75 (1.04–2.93) *
Hypertension Yes 1.00 (0.62–1.62) 0.70 (0.41–1.20) 1.00 (0.62–1.62) 0.80 (0.47–1.34)
PAH Yes 1.07 (0.60–1.92) 0.86 (0.46–1.58) 1.07 (0.60–1.92) 0.85 (0.47–1.55)
Sepsis Yes 5.65 (3.29–9.72) *** 3.13 (1.72–5.71) *** 5.65 (3.29–9.72) *** 5.23 (2.96–9.25) ***
CCI Mean (SD) 1.10 (0.95–1.27) 1.07 (0.91–1.26) 1.10 (0.95–1.27) 0.97 (0.78–1.22)
AECOPD
phenotypes based NTS and - - Reference Reference
on Exposure type NBMS-AECOPD
TS-AECOPD - - 2.18 (1.04–4.61) * 2.17 (1.02–4.63) *
BMS-AECOPD - - 4.82 (2.29–10.16) *** 5.28 (2.46–11.35) ***
TS and - - 6.35 (1.36–29.51) * 7.24 (1.53–34.29) *
BMS-AECOPD
AECOPD-NBE Reference Reference - -
AECOPD AECOPD-E 0.00 (0.00-Inf) 0.00 (0.00-Inf) - -
phenotypes based AECOPD-B 7.21 (3.47–14.97) *** 6.42 (3.06–13.46) *** - -
on pathology AECOPD-BE 3.53 (0.96–12.89) 3.84 (1.04–14.20) * - -
AECOPD-P 5.34 (2.54–11.20) *** 4.33 (2.01–9.30) *** - -
AECOPD-BC 3.30 (1.25–8.72) * 2.72 (1.00–7.38) * - -
* = p < 0.05, ** = p < 0.01, *** = p < 0.001, AECOPD: Acute exacerbation of chronic obstructive pulmonary diseases,
NBE: No bacterial infection and no eosinophilia, B: Bacterial infection, E: Eosinophilia and no bacterial infections,
BE: Bacterial infection with eosinophilia, P: Pneumonia, BC: Bronchiectasis, NTS and NBMS: Non-tobacco smoke
and non-biomass smoke, TS: Tobacco smoke, BMS: Biomass smoke, TS and BMS: Tobacco smoke and biomass
smoke, CCI: Charlson comorbidity index, PAH: Pulmonary hypertension, T1RF: Type 1 respiratory failure,
T2RF: Type 2 respiratory failure. The exposure is already segregated by gender: 99.2% of TS-AECOPD subjects are
males and 93.4% of BMS-AECOPD subjects are females; therefore, gender was not used in model 2.
Toxics 2022, 10, 667 11 of 19

Univariate Cox proportional-hazard regression analysis for survival in model 2 showed

that age higher than 60, type 2 respiratory failure, patients with sepsis, TS-AECOPD,
BMS-AECOPD, and TS and BMS-AECOPD were associated with poor survival. On multi-
variate Cox proportional-hazard regression analysis, type 2 respiratory failure [HR (95%
CI: 1.75 (1.04–2.93)], sepsis [HR (95% CI: 5.23 (2.96–9.25)], TS-AECOPD [HR 95% CI 2.17
(1.02–4.63)], BMS-AECOPD [HR 95% CI 5.28 (2.46–11.35)], and TS and BMS-AECOPD
[HR 95% CI 7.24 (1.53–34.29)] were found to be independently associated with poor sur-
vival (Model 2: Table 5). Since the exposure was already segregated by gender—99.2%
of TS-AECOPD subjects were males and 93.4% of BMS-AECOPD subjects were females—
gender was not used in model 2.
On binomial logistic regression analyses, AECOPD-B [10.66 (95% CI: 7.65–14.87)],
AECOPD-P [5.56 (95% CI: 4.04–7.6)], AECOPD-BE [4.32 (95% CI: 2.30–8.13)], AECOPD-BC
[3.341 (95% CI: 2.18–5.11)], and CCI [1.27 (95% CI: 1.14–1.42)] were found to be strong inde-
pendent predictors of type of ward admission (Table S4). On binomial logistic regression
analyses, AECOPD-BE [2.29 (95% CI: 1.29–4.06)], AECOPD-B [2.271 (95% CI: 1.69–3.05)],
AECOPD-P [2.09 (95% CI: 1.58–2.75)], AECOPD-BC [1.45 (95% CI: 0.99–2.09)], gender [1.44
(95% CI: 1.16–1.78)], and CCI [1.20 (95% CI: 1.10–1.31)] were found to be strong independent
predictors of length of hospital stay (Table S5).

4. Discussion
We observed six phenotypes of acute exacerbation of COPD which impact clinical
outcomes. To the best of our knowledge, this is the first attempt to compare the various
AECOPD phenotypes based on pathology and exposure, their characteristics, and their
clinical outcome in an LMIC country. We observed an overall mortality rate of 3.3%.
We observed the highest mortality in AECOPD-B (HR: 6.42), followed by AECOPD-P
(HR:4.33). The highest ICU admissions were for AECOPD-B (51%) and AECOPD-P (35.6%).
Besides AECOPD-E and AECOPD-BC, which had lower Charlson’s comorbidity indices,
comorbidities were similar across various phenotypes. Among subjects with AECOPD,
combined TS and BMS-AECOPD (HR 7.24) was observed to have a greater mortality risk
than BMS-AECOPD (HR 5.28), followed by TS-AECOPD (HR 2.17), and an additive effect
was observed. Female patients with AECOPD had a greater risk of death and poor outcome
than male patients.
Bacterial infection associated with COPD exacerbation, pneumonia associated with
COPD exacerbation, and sepsis are the risk factors most closely associated with a greater risk
of death. Lower respiratory tract infections, both acute and chronic, are frequent in patients
with AECOPD. Infections contribute considerably to these patients’ poor clinical course
and overall morbidity and mortality [56,57]. AECOPD patients have an impaired response
to microbial colonization and infection. These impaired responses, such as impaired
alveolar macrophage and toll-like receptor activity, increase infection vulnerability and
promote an oxidative stress response that injures lung tissue [58,59]. Bacterial infections
are responsible for more than 50% of AECOPD exacerbations [60]. Bacterial load in the
lungs of AECOPD patients is an essential determinant of airway inflammation. Increased
concentration of pathogens is directly correlated with greater intensity of neutrophilic
airway inflammation [60,61]. Another model of exacerbation pathogenesis suggests that
acquiring novel bacterial strains is a major driver of acute exacerbations [56,62]. Among
different AECOPD phenotypes, the highest mortality rate was observed in the AECOPD-B
phenotype (11.2%), with the highest hazard ratio of 6.42 compared to other AECOPD
phenotypes. Other studies evaluating mortality rates in AECOPD with bacterial infections
range from 2.4% to 8.2% [27,28]. The AECOPD-B phenotype was also associated with a
longer duration of hospitalization, and had the highest risk of ICU admissions compared to
other AECOPD phenotypes. Other studies evaluating the length of hospital stay ranged in
their evaluation from 10 to 13 days [27–29], but had fewer ICU admissions than our study,
with 51% of AECOPD-B patients admitted to ICU.
Toxics 2022, 10, 667 12 of 19

Pneumonia is a significant cause of hospitalization and mortality, especially among

AECOPD patients, and is linked to abnormal host-defense mechanisms [63–65]. A study by
Gutierrez et al. analyzed sputum samples from pneumonia patients, and compared them
with AECOPD patients and patients with both pneumonia and AECOPD. They observed
that the microenvironment present in the lung modulates the activation of macrophages,
which may lead to disparities in cytokine generation and specific macrophage activation
when AECOPD and pneumonia are present simultaneously; this can cause different in-
flammatory responses leading to different outcomes [65]. Furthermore, a study by Huerta
et al. found that, compared to other cohorts, patients with AECOPD-P had a higher level
of Interleukin 6, tumor necrosis factor-α, C-reactive protein, and procalcitonin [30]. Our
cohort’s prevalence of AECOPD-P was 14.1%, and they had the second highest mortality
rate at 7.8%. Various studies have shown that AECOPD-P has mortality rates ranging from
3.4% to 13.2% [30–36]. In our study, AECOPD subjects with pneumonia had a significantly
higher mortality risk than AECOPD-NBE and AECOPD-E as assessed by Kaplan–Meier
analysis (30-day mortality). Similar results were also seen in other studies investigating
AECOPD-P [37,38]. AECOPD-P had a longer duration of hospitalization, between 4 to
10 days, which was twice that of AECOPD-NBE. The length of hospitalization in other
studies varied from 7 days to 16 days [30–34]. The percentage of ICU admission was signifi-
cantly lower in previous studies, ranging from 2.6% to 26%, compared to our study (35.6%),
which could be due to a higher percentage of sepsis patients (17.2%) among the AECOPD-P
phenotype in our study. According to several studies, sepsis is more likely to occur in
AECOPD patients due to corticosteroids, underlying comorbidities, and possibly compro-
mised barrier function, leading to an increased risk of developing pneumonia [66–68]. A
study performed by Chen et al. studied the impact of sepsis on COPD patients’ outcomes,
and they identified that COPD patients with sepsis had a higher risk of pneumonia, severe
exacerbations, and mortality compared to COPD patients without sepsis [69].
The role of eosinophilic inflammation in the exacerbation of COPD is not clear. Sub-
jects with AECOPD and eosinophilia have better corticosteroid responsiveness [70–72] and
eosinophilic AECOPD patients have better outcomes [23]. The prevalence of AECOPD-E in
our cohort was 17.7%, with zero mortality, and these patients had the best outcomes compared
to other phenotypes. Several studies have observed lower mortality rates in eosinophilic
patients ranging from 0% to 1% [20–23] similar to our study, which could be due to fewer
comorbidities [73], shorter length of hospital stay (2 days to 8.81 days) [24,25,74,75], and
less-frequent admissions [75–77] in eosinophilic patients than other phenotypes. The number
of ICU admissions ranged from 1.32% to 11.7% [21,24,26,78–80], similar to our study, which
had ICU admission in 2.1% of subjects with AECOPD-E.
Subjects with AECOPD and both eosinophilia and bacterial infection (AECOPD-BE)
formed the smallest group (2.4%) in our study, with a mortality rate of 5.7%. It had the
third highest ICU admission (30.2%) with odds of 4.33 (95% CI: 2.3–8.13) and the length of
hospital stay ranged from 4 days to 9 days with odds of 2.29 (95% CI: 1.29–4.06) compared
to AECOPD-NBE. We could not find any studies showing a direct relationship between
AECOPD and bacterial infection and eosinophilia. Conversely, we found several studies
showing an inverse relationship between eosinophil count and bacterial load, suggesting
that the presence of less than 2% eosinophils in AECOPD events may indicate bacterial
infection [81–83]. It is unclear what causes the drop in eosinophil levels during bacterial
infection. Still, possible reasons might be the adrenal glucocorticoid activation in reaction to
the stress of bacterial infection, or the rapid accumulation of eosinophils at the inflammatory
site possibly causing a decrease in the number of eosinophils in circulation [84,85]
Mitochondrial DNA which plays a vital role in regulating cellular metabolism, sig-
naling pathways, and cell death [86] can be released by eosinophils as an innate immune
response to pathogens to form extracellular mitochondrial DNA traps and express specific
pattern-recognition receptors, such as Toll-like receptor 4, which can recognize pathogens
and trigger an immune response [87,88]. Eosinophil granule proteins also possess bacte-
ricidal activity [89]. Furthermore, high levels of cell-free mitochondrial DNA have been
Toxics 2022, 10, 667 13 of 19

found in the plasma of former smokers affected by COPD [90], in the serum of mice that
developed emphysema induced by chronic exposure to cigarette smoke for 6 months [90],
and also in the bronchoalveolar lavage of mice acutely exposed to cigarette smoke [91]. In
addition, in a small single-center study, high levels of total cell-free DNA were detected
in the plasma of patients with COPD exacerbations admitted to the hospital, and were
associated with an increased risk of 5-year mortality [92]. It has been also shown that
cells other than eosinophils could release mitochondrial DNA, including neutrophils [93].
In the context of COPD and its main risk factor (cigarette smoke), it has been found that
human bronchial alveolar cells exposed to cigarette smoke release mitochondrial DNA by
extracellular vesicles and cells debris, and this, in turn, may trigger the upregulation of
typical proinflammatory cytokines observed in COPD [90].
Bronchiectasis is highly prevalent in AECOPD patients, ranging from 4% to 72% [94].
It is associated with severe bronchial inflammation, higher functional impairment, higher
frequency and severity of exacerbations, and increased hospitalization in AECOPD pa-
tients [95–97]. The prevalence of AECOPD-BC in our study was 7.7%, with a mortality of
4.2%. We observed a similar length of hospital stay (4 to 8 days) in our AECOPD-BC cohort
compared to other studies, which ranged from 5.7 days to 9.6 days [39–41]. Sánchez-Muñoz
et al. observed 5.5% ICU admissions in the AECOPD-BC cohort [41] in contrast, in our
study, we observed 23.2% ICU admissions in the AECOPD-BC cohort. Our study found
that the AECOPD-BC phenotype was higher in female than in male patients, similar to
observations made in other similar studies [98–101].
One of the important risk factors for non-smoking COPD is exposure to biomass
fuels [102], which are critical for activities of daily living such as cooking and heating,
especially in developing nations [103]; almost 3 billion people worldwide use biomass fuels
as their primary source of energy. Biomass fuels account for 50–90% of household energy
in many developing countries. Biomass combustion fumes contain several pollutants
with potential to cause long-term damage to the lungs. This includes particulate matter,
volatile organic compounds such as and formaldehyde and benzene, and other organic
matter, including polycyclic aromatic hydrocarbons such as benzopyrene [54]. The US
Environmental Protection Agency has established National Ambient Air Quality Standards,
and the recommended daily average of PM10 is below 150 µg m−3 . The recommended
annual average is below 50 µg m−3 . In homes that use biomass fuels, the average PM10
concentrations vary between 200 to 5000 µg m−3 , depending on the presence of a chimney,
ventilation (windows, cooking with doors open), and the type of fuel and stove. Cigarette
smoke contains more than 4000 chemicals, including many toxic compounds and well-
known risk factors for developing COPD [44,104–107].
We observed the highest mortality rates in BMS-AECOPD (7.1%), followed by TS and
BMS-AECOPD (6.3%). Various studies have shown mortality rates for TS-AECOPD ranging
from 6.8% to 29% [47,108–113]; for BMS-AECOPD, ranging from 8.4% to 18% [47,112];
and for NTS and NBMS-AECOPD, ranging from 3.8% to 24.67% [108–110,113]. Biomass
exposure was predominantly seen in females, and included 93.4% of females and 6.6% of
males. Among females exposed to biomass, mortality rates were 7.3% versus 3.6% among
males exposed to biomass. A higher number of subjects with BMS-AECOPD had diabetes
mellitus, hypertension, obesity, obstructive sleep apnea, and renal failure than subjects
with TS and BMS-AECOPD, who were all males. Female gender was an independent risk
factor for AECOPD-related mortality in our study, and few reasons have been identified
from previous studies. Females have smaller airways and lungs [114]; there are gender
differences in lung physiology and microbiota composition, which may influence the
severity and progression of chronic respiratory disease states [100,115]; the respiratory
microbiome is vulnerable to various host immunological and inflammatory effects, and
seems to have sex-specific characteristics [116,117]; and chronic persistent inflammation is
thought to be more harmful in females, increasing tissue damage and worsening illness
severity [118]. The gender divide in human health and disease could be primarily explained
by variations in genetics and sex steroid hormones, both in kind and concentration [119].
Toxics 2022, 10, 667 14 of 19

There is a steady decline in lung function with advancing age, which increases the risk
of dyspnea and the prevalence of chronic pulmonary disorders in older people [120,121].
The prevalence of AECOPD is two to three times higher in patients older than 60. With
increasing age, comorbidities also increase, but these comorbidities manifest earlier in
AECOPD patients than in non-COPD patients [122]. The aging process in the lungs and
AECOPD shares many similarities. Many signs of aging are present in AECOPD, indicating
that accelerated aging may be a pathogenic factor in AECOPD [123].
To our knowledge, this is one of the most extensive studies in India on the survival of
different phenotypes of AECOPD based on both pathologies and exposure. The study’s
main drawback is that it has a monocentric design, making it harder for our findings to gen-
eralize. Only routine bacterial cultures were performed for bacterial identification. Other
causes of AECOPD, such as viral AECOPD, were not investigated. Sputum induction was
not performed; therefore, further characterization of AECOPD could not be achieved. In the
future, more advanced techniques—such as the Biofire test—to identify viruses, bacteria,
parasites, yeast, and antimicrobial resistance genes, in addition to sputum induction, can
help to identify AECOPD phenotypes with even greater resolution.

5. Conclusions
In conclusion, we observed significant gender differences, with females having a
much higher mortality risk than males. AECOPD-B patients, followed by AECOPD-P
patients, were at higher mortality risk and had a more-extended hospital stay. Subjects with
biomass exposure and who smoked, followed by subjects with biomass exposure, were at
higher mortality risk. Different phenotypes have different impacts on AECOPD clinical
outcomes. A better understanding of AECOPD phenotypes could contribute to developing
an algorithm for the precise management of different phenotypes.

Supplementary Materials: The following supporting information can be downloaded at:

https://www.mdpi.com/article/10.3390/toxics10110667/s1, Table S1: Clinical characteristics of
AECOPD subjects based on gender; Table S2: Clinical Characteristics of AECOPD subjects based on
pathology with gender stratified; Table S3: Clinical Characteristics of AECOPD subjects based on
exposure type with gender stratified; Table S4: Binomial logistic regression for the type of ward as an
outcome; Table S5: Binomial logistic regression for the length of hospital stays as an outcome.
Author Contributions: M.K.U., S.U., K.G. and P.A.M. were involved in conceptualizing the research
idea and creating the research design. M.K.U., A.P., J.B.S. and P.V. were involved in the acquisition of
data and analysis. M.K.U., A.P., J.B.S., P.V., S.U., K.G. and P.A.M. were involved in the interpretation
of data and verified the underlying data. M.K.U., A.P., J.B.S., P.V. and P.A.M. were involved in
drafting the manuscript’s intellectual content. P.A.M., S.U. and K.G. were involved in the critical
revision of the manuscript’s intellectual content. M.K.U., A.P., P.A.M., S.U. and K.G. managed the
submission process. All authors had full access to all the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis. All authors have read and agreed to
the published version of the manuscript.
Funding: This work was supported by the National Institutes of Health (NIH), Fogarty International
Center, Global Infectious Disease Research Training program (GID) [Grant D43TW010332-01A1 to
PAM], The Wellcome Trust DBT India Alliance [Grant IA/TSG/19/1/600026 to PAM], and Swedish
Heart-Lung Foundation (S.U.: 20210548; K.G.: 20200776). The funders had no role in the study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Institutional Review Board Statement: No animals were used for studies that were based on this
research. This study was approved by the Institutional Ethics Committee of JSS Medical College,
Mysuru (Approval number: JSSMC/IEC/18.02.2022/24NCT/2021-22).
Informed Consent Statement: Patient consent was waived because this was a retrospective study.
Data Availability Statement: All data generated or analyzed during this study are included in this
published article and are available from the corresponding author upon reasonable request.
Conflicts of Interest: The authors declare that this article’s content has no conflict of interest.
Toxics 2022, 10, 667 15 of 19

References
1. Pauwels, R.A.; Buist, A.S.; Calverley, P.M.A.; Jenkins, C.R.; Hurd, S.S. GOLD Scientific Committee Global Strategy for the
Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Global Initiative for Chronic
Obstructive Lung Disease (GOLD) Workshop Summary. Am. J. Respir. Crit. Care Med. 2001, 163, 1256–1276. [CrossRef] [PubMed]
2. GOLD Report 2022. 2022; pp. 1–165. Available online: https://goldcopd.org/2022-gold-reports-2/ (accessed on 1 November 2022).
3. Varmaghani, M.; Dehghani, M.; Heidari, E.; Sharifi, F.; Saeedi Moghaddam, S.; Farzadfar, F. Global Prevalence of Chronic
Obstructive Pulmonary Disease: Systematic Review and Meta-Analysis. East. Mediterr. Health J. 2019, 25, 47–57. [CrossRef]
[PubMed]
4. Grigsby, M.; Siddharthan, T.; Chowdhury, M.; Siddiquee, A.; Rubinstein, A.; Sobrino, E.; Miranda, J.J.; Bernabe-Ortiz, A.; Alam,
D.; Checkley, W. Socioeconomic Status and COPD among Low- and Middle-Income Countries. Int. J. Chron. Obstruct. Pulmon.
Dis. 2016, 11, 2497–2507. [CrossRef]
5. Buist, A.S.; McBurnie, M.A.; Vollmer, W.M.; Gillespie, S.; Burney, P.; Mannino, D.M.; Menezes, A.M.; Sullivan, S.D.; Lee, T.A.;
Weiss, K.B.; et al. International Variation in the Prevalence of COPD (The BOLD Study): A Population-Based Prevalence Study.
Lancet 2007, 370, 741–750. [CrossRef]
6. World Health Organization. World Health Organization-Burden of COPD. Newsroom. 2022; p. 1. Available online:
http://www.who.int/respiratory/copdburden/en/ (accessed on 1 November 2022).
7. World Health Organization. World Health Organization-The Top 10 Causes of Death. Newsroom. 2020; p. 1. Available online:
https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (accessed on 1 November 2022).
8. Viegi, G.; Maio, S.; Fasola, S.; Baldacci, S. Global Burden of Chronic Respiratory Diseases. J. Aerosol Med. Pulm. Drug Deliv. 2020,
33, 171–177. [CrossRef] [PubMed]
9. Soriano, J.B.; Kendrick, P.J.; Paulson, K.R.; Gupta, V.; Abrams, E.M.; Adedoyin, R.A.; Adhikari, T.B.; Advani, S.M.; Agrawal,
A.; Ahmadian, E.; et al. Prevalence and Attributable Health Burden of Chronic Respiratory Diseases, 1990–2017: A Systematic
Analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med. 2020, 8, 585–596. [CrossRef]
10. Halpin, D.M.G.; Celli, B.R.; Criner, G.J.; Frith, P.; López Varela, M.V.; Salvi, S.; Vogelmeier, C.F.; Chen, R.; Mortimer, K.; Montes de
Oca, M.; et al. The GOLD Summit on Chronic Obstructive Pulmonary Disease in Low- And Middle-Income Countries. Int. J.
Tuberc. Lung Dis. 2019, 23, 1131–1141. [CrossRef] [PubMed]
11. Salvi, S.; Kumar, G.A.; Dhaliwal, R.S.; Paulson, K.; Agrawal, A.; Koul, P.A.; Mahesh, P.A.; Nair, S.; Singh, V.; Aggarwal, A.N.; et al.
The Burden of Chronic Respiratory Diseases and Their Heterogeneity across the States of India: The Global Burden of Disease
Study 1990–2016. Lancet Glob. Health 2018, 6, 1363–1374. [CrossRef]
12. Indian Council of Medical Research; Public Health Foundation of India; Institute for Health Metrics and Evaluation India. India:
Health of the Nation’s States. The India State-Level Disease Burden Initiative: Disease Burden Trends in the States of India 1990
to 2016. 2017, pp. 1–214. Available online: https://www.healthdata.org/ (accessed on 1 November 2022).
13. Papi, A. Pathophysiology of Exacerbations of Chronic Obstructive Pulmonary Disease. Proc. Am. Thorac. Soc. 2006, 3, 245–251.
[CrossRef]
14. 1Barberà, J.A.; Roca, J.; Ferrer, A.; Félez, M.A.; Díaz, O.; Roger, N.; Rodriguez-Roisin, R. Mechanisms of Worsening Gas Exchange
during Acute Exacerbations of Chronic Obstructive Pulmonary Disease. Eur. Respir. J. 1997, 10, 1285–1291. [CrossRef]
15. Vogelmeier, C.F.; Criner, G.J.; Martinez, F.J.; Anzueto, A.; Barnes, P.J.; Bourbeau, J.; Celli, B.R.; Chen, R.; Decramer, M.; Fabbri,
L.M.; et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report:
GOLD Executive Summary. Eur. Respir. J. 2017, 195, 557–582. [CrossRef]
16. Seemungal, T.A.R.; Donaldson, G.C.; Paul, E.A.; Bestall, J.C.; Jeffries, D.J.; Wedzicha, J.A. Effect of Exacerbation on Quality of Life
in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 1998, 157 Pt 1, 1418–1422. [CrossRef]
17. Miravitlles, M.; Ribera, A. Understanding the Impact of Symptoms on the Burden of COPD. Respir. Res. 2017, 18, 1–11. [CrossRef]
[PubMed]
18. Han, M.K.; Agusti, A.; Calverley, P.M.; Celli, B.R.; Criner, G.; Curtis, J.L.; Fabbri, L.M.; Goldin, J.G.; Jones, P.W.; MacNee, W.; et al.
Chronic Obstructive Pulmonary Disease Phenotypes: The Future of COPD. Am. J. Respir. Crit. Care Med. 2010, 182, 598–604.
[CrossRef] [PubMed]
19. Lopez-Campos, J.L.; Agustí, A. Heterogeneity of Chronic Obstructive Pulmonary Disease Exacerbations: A Two-Axes Classifica-
tion Proposal. Lancet Respir. Med. 2015, 3, 729–734. [CrossRef]
20. Wu, C.-W.; Lan, C.-C.; Hsieh, P.-C.; Tzeng, I.-S.; Wu, Y.-K. Role of Peripheral Eosinophilia in Acute Exacerbation of Chronic
Obstructive Pulmonary Disease. World J. Clin. Cases 2020, 8, 2727–2737. [CrossRef] [PubMed]
21. Jabarkhil, A.; Moberg, M.; Janner, J.; Petersen, M.N.; Jensen, C.B.; Henrik Ängquist, L.; Vestbo, J.; Jess, T.; Porsbjerg, C. Elevated
Blood Eosinophils in Acute COPD Exacerbations: Better Short- and Long-Term Prognosis. Eur. Clin. Respir. J. 2020, 7, 1–9.
[CrossRef]
22. Li, Q.; Larivée, P.; Courteau, J.; Couillard, S.; Poder, T.G.; Carrier, N.; Bélanger, M.; Vanasse, A. Greater Eosinophil Counts at First
COPD Hospitalization Are Associated with More Readmissions and Fewer Deaths. Int. J. COPD 2019, 14, 331–341. [CrossRef]
23. Ho, J.; He, W.; Chan, M.T.V.; Tse, G.; Liu, T.; Wong, S.H.; Leung, C.C.H.; Wong, W.T.; Tsang, S.; Zhang, L.; et al. Eosinophilia and
Clinical Outcome of Chronic Obstructive Pulmonary Disease: A Meta-Analysis. Sci. Rep. 2017, 7, 1–10. [CrossRef]
Toxics 2022, 10, 667 16 of 19

24. Salturk, C.; Karakurt, Z.; Takir, H.; Gungor, G.; Kargin, F.; Mocin, O.; Adiguzel, N.; Sari, R.; Celik, E.; Tuncay, E.; et al. Does
Eosinophilic COPD Exacerbation Have a Better Patient Outcome than Non-Eosinophilic in the Intensive Care Unit? Int. J. Chron.
Obstruct. Pulmon. Dis. 2015, 10, 1837–1846. [CrossRef]
25. Bafadhel, M.; Greening, N.J.; Harvey-Dunstan, T.C.; Williams, J.E.A.; Morgan, M.D.; Brightling, C.E.; Hussain, S.F.; Pavord,
I.D.; Singh, S.J.; Steiner, M.C. Blood Eosinophils and Outcomes in Severe Hospitalized Exacerbations of COPD. Chest 2016, 150,
320–328. [CrossRef] [PubMed]
26. Kandemir, Y.; Doğan, N.Ö.; Yaka, E.; Pekdemir, M.; Yılmaz, S. Clinical Characteristics of Neutrophilic, Eosinophilic and
Mixed-Type Exacerbation Phenotypes of COPD. Am. J. Emerg. Med. 2021, 45, 237–241. [CrossRef] [PubMed]
27. Boixeda, R.; Almagro, P.; Diez-Manglano, J.; Cabrera, F.; Recio, J.; Martin-Garrido, I.; Soriano, J.B. Bacterial Flora in the Sputum
and Comorbidity in Patients with Acute Exacerbations of COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2015, 10, 2581–2591.
[CrossRef] [PubMed]
28. Groenewegen, K.H.; Wouters, E.F.M. Bacterial Infections in Patients Requiring Admission for an Acute Exacerbation of COPD; a
1-Year Prospective Study. Respir. Med. 2003, 97, 770–777. [CrossRef]
29. Fei, G.; Dai, M.-Y.; Qiao, J.-P.; Xu, Y.-H. Respiratory Infectious Phenotypes in Acute Exacerbation of COPD: An Aid to Length of
Stay and COPD Assessment Test. Int. J. Chron. Obstruct. Pulmon. Dis. 2015, 10, 2257–2263. [CrossRef] [PubMed]
30. Huerta, A.; Crisafulli, E.; Menéndez, R.; Martínez, R.; Soler, N.; Guerrero, M.; Montull, B.; Torres, A. Pneumonic and Nonpneu-
monic Exacerbations of COPD: Inflammatory Response and Clinical Characteristics. Chest 2013, 144, 1134–1142. [CrossRef]
[PubMed]
31. Yu, S.; Fang, Q.; Li, Y. Independent Factors Associated with Pneumonia among Hospitalized Patients with Acute Exacerbations of
Chronic Obstructive Pulmonary Disease. Medicine (Baltimore) 2018, 97, 1–6. [CrossRef]
32. Dai, R.X.; Kong, Q.H.; Mao, B.; Xu, W.; Tao, R.J.; Wang, X.R.; Kong, Q.Y.; Xu, J.F. The Mortality Risk Factor of Community
Acquired Pneumonia Patients with Chronic Obstructive Pulmonary Disease: A Retrospective Cohort Study. BMC Pulm. Med.
2018, 18, 1–10. [CrossRef]
33. Jeong, S.W.; Lee, J.H.; Choi, K.J.; Hwangbo, Y.; Kim, Y.Y.; Lee, Y.J.; Yoon, W.K.; Kim, M.; Cha, S.I.; Park, J.Y.; et al. Comparisons
of Clinical Characteristics and Outcomes in COPD Patients Hospitalized with Community-Acquired Pneumonia and Acute
Exacerbation. Tuberc. Respir. Dis. 2010, 69, 31–38. [CrossRef]
34. Søgaard, M.; Madsen, M.; Løkke, A.; Hilberg, O.; Sørensen, H.T.; Thomsen, R.W. Incidence and Outcomes of Patients Hospitalized
with COPD Exacerbation with and without Pneumonia. Int. J. Chron. Obstruct. Pulmon. Dis. 2016, 11, 455–465. [CrossRef]
35. Lieberman, D.; Lieberman, D.; Gelfer, Y.; Varshavsky, R.; Dvoskin, B.; Leinonen, M.; Friedman, M.G. Pneumonic vs Nonpneumonic
Acute Exacerbations of COPD. Chest 2002, 122, 1264–1270. [CrossRef]
36. Sharafkhaneh, A.; Spiegelman, A.M.; Main, K.; Tavakoli-Tabasi, S.; Lan, C.; Musher, D. Mortality in Patients Admitted for
Concurrent COPD Exacerbation and Pneumonia. COPD J. Chronic Obstr. Pulm. Dis. 2017, 14, 23–29. [CrossRef] [PubMed]
37. Shin, B.; Kim, S.H.; Yong, S.J.; Lee, W.Y.; Park, S.; Lee, S.J.; Lee, S.J.; Lee, M.K. Early Readmission and Mortality in
Acute Exacerbation of Chronic Obstructive Pulmonary Disease with Community-Acquired Pneumonia. Chron. Respir.
Dis. 2018, 16, 1–12. [CrossRef] [PubMed]
38. Restrepo, M.I.; Mortensen, E.M.; Pugh, J.A.; Anzueto, A. COPD Is Associated with Increased Mortality in Patients with
Community-Acquired Pneumonia. Eur. Respir. J. 2006, 28, 346–351. [CrossRef] [PubMed]
39. Mao, B.; Lu, H.-W.; Li, M.-H.; Fan, L.-C.; Yang, J.-W.; Miao, X.-Y.; Xu, J.-F. The Existence of Bronchiectasis Predicts Worse Prognosis
in Patients with COPD. Sci. Rep. 2015, 5, 10961. [CrossRef] [PubMed]
40. Molino, A.; Vitale, C.; Valente, T.; Amato, M.D.; Mormile, M. Impact of Bronchiectasis on COPD Exacerbations. Int. J. Thorax 2018,
1, 1–7.
41. Sánchez-Muñoz, G.; Lopez-de-Andrés, A.; Hernández-Barrera, V.; Jiménez-García, R.; Pedraza-Serrano, F.; Puente-Maestu, L.;
de Miguel-Díez, J. Bronchiectasis in Patients Hospitalized with Acute Exacerbation of COPD in Spain: Influence on Mortality,
Hospital Stay, and Hospital Costs (2006-2014) According to Gender. PLoS ONE 2019, 14, e0211222. [CrossRef]
42. MacDonald, M.I.; Osadnik, C.R.; Bulfin, L.; Leahy, E.; Leong, P.; Shafuddin, E.; Hamza, K.; King, P.T.; Bardin, P.G. MULTI-
PHACET: Multidimensional Clinical Phenotyping of Hospitalised Acute COPD Exacerbations. ERJ Open Res. 2021, 7, 00198–02021.
[CrossRef]
43. Zhou, A.; Zhou, Z.; Zhao, Y.; Chen, P. The Recent Advances of Phenotypes in Acute Exacerbations of COPD. Int. J. Chron. Obstruct.
Pulmon. Dis. 2017, 12, 1009–1018. [CrossRef]
44. Salvi, S. Tobacco Smoking and Environmental Risk Factors for Chronic Obstructive Pulmonary Disease. Clin. Chest
Med. 2014, 35, 17–27. [CrossRef]
45. Ramírez-Venegas, A.; Montiel-Lopez, F.; Falfan-Valencia, R.; Pérez-Rubio, G.; Sansores, R.H. The “Slow Horse Racing Effect”
on Lung Function in Adult Life in Chronic Obstructive Pulmonary Disease Associated to Biomass Exposure. Front. Med.
2021, 8, 700836. [CrossRef] [PubMed]
46. Shetty, B.S.P.; D’Souza, G.; Padukudru Anand, M. Effect of Indoor Air Pollution on Chronic Obstructive Pulmonary Disease
(COPD) Deaths in Southern Asia—A Systematic Review and Meta-Analysis. Toxics 2021, 9, 85. [CrossRef] [PubMed]
47. Ramírez-Venegas, A.; Sansores, R.H.; Pérez-Padilla, R.; Regalado, J.; Velázquez, A.; Sánchez, C.; Mayar, M.E. Survival of
Patients with Chronic Obstructive Pulmonary Disease Due to Biomass Smoke and Tobacco. Am. J. Respir. Crit. Care Med.
2006, 173, 393–397. [CrossRef]
Toxics 2022, 10, 667 17 of 19

48. Camp, P.G.; Ramirez-Venegas, A.; Sansores, R.H.; Alva, L.F.; McDougall, J.E.; Sin, D.D.; Pare, P.D.; Muller, N.L.; Silva, C.I.S.;
Rojas, C.E.; et al. COPD Phenotypes in Biomass Smoke- versus Tobacco Smoke-Exposed Mexican Women. Eur. Respir. J.
2014, 43, 725–734. [CrossRef] [PubMed]
49. Tabyshova, A.; Hurst, J.R.; Soriano, J.B.; Checkley, W.; Wan-Chun Huang, E.; Trofor, A.C.; Flores-Flores, O.; Alupo, P.; Gianella, G.;
Ferdous, T.; et al. Gaps in COPD Guidelines of Low- and Middle-Income Countries. Chest 2021, 159, 575–584. [CrossRef]
50. Crisafulli, E.; Barbeta, E.; Ielpo, A.; Torres, A. Management of Severe Acute Exacerbations of COPD: An Updated Narrative
Review. Multidiscip. Respir. Med. 2018, 13, 36. [CrossRef] [PubMed]
51. Charlson, M.E.; Pompei, P.; Ales, K.L.; MacKenzie, C.R. A New Method of Classifying Prognostic Comorbidity in Longitudinal
Studies: Development and Validation. J. Chronic Dis. 1987, 40, 373–383. [CrossRef]
52. Brusselle, G.; Pavord, I.D.; Landis, S.; Pascoe, S.; Lettis, S.; Morjaria, N.; Barnes, N.; Hilton, E. Blood Eosinophil Levels as a
Biomarker in COPD. Respir. Med. 2018, 138, 21–31. [CrossRef]
53. Apte, K.; Salvi, S. Household Air Pollution and Its Effects on Health. F1000Research 2016, 5, 2593. [CrossRef]
54. Smith, K.R. Biofuels, Air Pollution, and Health: A Global Review; Springer: Boston, MA, USA, 1987; ISBN 978-1-4612-8231-0.
55. Smith, K.R.; Apte, M.G.; Yuqing, M.; Wongsekiarttirat, W.; Kulkarni, A. Air Pollution and the Energy Ladder in Asian Cities.
Energy 1994, 19, 587–600. [CrossRef]
56. Veeramachaneni, S.B.; Sethi, S. Pathogenesis of Bacterial Exacerbations of COPD. COPD J. Chronic Obstr. Pulm. Dis. 2006, 3, 109–115.
[CrossRef] [PubMed]
57. Ritchie, A.I.; Wedzicha, J.A. Definition, Causes, Pathogenesis, and Consequences of Chronic Obstructive Pulmonary Disease
Exacerbations. Clin. Chest Med. 2020, 41, 421–438. [CrossRef] [PubMed]
58. Berenson, C.S.; Kruzel, R.L.; Eberhardt, E.; Dolnick, R.; Minderman, H.; Wallace, P.K.; Sethi, S. Impaired Innate Immune Alveolar
Macrophage Response and the Predilection for Copd Exacerbations. Thorax 2014, 69, 811–818. [CrossRef] [PubMed]
59. King, P.T.; Sharma, R.; O’Sullivan, K.; Selemidis, S.; Lim, S.; Radhakrishna, N.; Lo, C.; Prasad, J.; Callaghan, J.; McLaughlin, P.;
et al. Nontypeable Haemophilus Influenzae Induces Sustained Lung Oxidative Stress and Protease Expression. PLoS ONE 2015,
10, e0120371. [CrossRef] [PubMed]
60. Sethi, S.; Murphy, T.F. Infection in the Pathogenesis and Course of Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2008,
359, 2355–2365. [CrossRef] [PubMed]
61. Hill, A.T.; Campbell, E.J.; Hill, S.L.; Bayley, D.L.; Stockley, R.A. Association between Airway Bacterial Load and Markers of
Airway Inflammation in Patients with Stable Chronic Bronchitis. Am. J. Med. 2000, 109, 288–295. [CrossRef]
62. Sethi, S.; Evans, N.; Grant, B.J.B.; Murphy, T.F. New Strains of Bacteria and Exacerbations of Chronic Obstructive Pulmonary
Disease. N. Engl. J. Med. 2002, 347, 465–471. [CrossRef]
63. Soriano, J.B.; Visick, G.T.; Muellerova, H.; Payvandi, N.; Hansell, A.L. Patterns of Comorbidities in Newly Diagnosed COPD and
Asthma in Primary Care. Chest 2005, 128, 2099–2107. [CrossRef]
64. Müllerova, H.; Chigbo, C.; Hagan, G.W.; Woodhead, M.A.; Miravitlles, M.; Davis, K.J.; Wedzicha, J.A. The Natural History
of Community-Acquired Pneumonia in COPD Patients: A Population Database Analysis. Respir. Med. 2012, 106, 1124–1133.
[CrossRef]
65. Gutierrez, P.; Closa, D.; Piñer, R.; Bulbena, O.; Menéndez, R.; Torres, A. Macrophage Activation in Exacerbated COPD with and
without Community-Acquired Pneumonia. Eur. Respir. J. 2010, 36, 285–291. [CrossRef]
66. Chaturvedi, S.; Kumar, A.; Sapkota, S.; Rojas, S.; Carla Krissel Badiola, M.; Patel, P.; Upadhyaya, A.; Shah, H.; Karki, A. Impact of
Sepsis on Outcomes of Hospitalizations Due to COPD. Chest 2021, 160, A1906. [CrossRef]
67. Hasselbacher, D.A.; Mannino, D.M.; Berger, R. Patients with Chronic Obstructive Pulmonary Disease Are at Higher Risk of Sepsis.
Chest 2005, 128, 378S. [CrossRef]
68. Ernst, P.; Coulombe, J.; Brassard, P.; Suissa, S. The Risk of Sepsis with Inhaled and Oral Corticosteroids in Patients with COPD.
COPD J. Chronic Obstr. Pulm. Dis. 2017, 14, 137–142. [CrossRef]
69. Chen, C.-H.; Lai, C.-C.; Wang, Y.-H.; Wang, C.-Y.; Wang, H.-C.; Yu, C.-J.; Chen, L. Taiwan Clinical Trial Consortium for Respiratory
Diseases (TCORE) The Impact of Sepsis on the Outcomes of COPD Patients: A Population-Based Cohort Study. J. Clin. Med. 2018,
7, 393. [CrossRef] [PubMed]
70. Leigh, R.; Pizzichini, M.M.M.; Morris, M.M.; Maltais, F.; Hargreave, F.E.; Pizzichini, E. Stable COPD: Predicting Benefit from
High-Dose Inhaled Corticosteroid Treatment. Eur. Respir. J. 2006, 27, 964–971. [CrossRef]
71. Bafadhel, M.; McKenna, S.; Terry, S.; Mistry, V.; Reid, C.; Haldar, P.; McCormick, M.; Haldar, K.; Kebadze, T.; Duvoix, A.; et al.
Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Identification of Biologic Clusters and Their Biomarkers. Am. J.
Respir. Crit. Care Med. 2011, 184, 662–671. [CrossRef]
72. Pascoe, S.; Locantore, N.; Dransfield, M.T.; Barnes, N.C.; Pavord, I.D. Blood Eosinophil Counts, Exacerbations, and Response to
the Addition of Inhaled Fluticasone Furoate to Vilanterol in Patients with Chronic Obstructive Pulmonary Disease: A Secondary
Analysis of Data from Two Parallel Randomised Controlled Trials. Lancet Respir. Med. 2015, 3, 435–442. [CrossRef]
73. Disantostefano, R.L.; Hinds, D.; Van Le, H.; Barnes, N.C. Relationship between Blood Eosinophils and Clinical Characteristics in a
Cross-Sectional Study of a US Population-Based COPD Cohort. Respir. Med. 2016, 112, 88–96. [CrossRef]
74. Holland, M.; Alkhalil, M.; Chandromouli, S.; Janjua, A.; Babores, M. Eosinopenia as a Marker of Mortality and Length of Stay in
Patients Admitted with Exacerbations of Chronic Obstructive Pulmonary Disease. Respirology 2010, 15, 165–167. [CrossRef]
Toxics 2022, 10, 667 18 of 19

75. Duman, D.; Aksoy, E.; Agca, M.C.; Kocak, N.D.; Ozmen, I.; Akturk, U.A.; Gungor, S.; Tepetam, F.M.; Eroglu, S.A.; Oztas, S.; et al.
The Utility of Inflammatory Markers to Predict Readmissions and Mortality in COPD Cases with or without Eosinophilia. Int. J.
COPD 2015, 11, 2469–2478. [CrossRef]
76. Villalobos, R.; Magallanes, J.; David-Wang, A. P143 Blood Eosinophilia as Predictor for Patient Outcomes in COPD Exacerbations:
A Systematic Review and Meta-Analysis. Thorax 2016, 71, 160. [CrossRef]
77. Gonzalez-Barcala, F.J.; San-Jose, M.E.; Nieto-Fontarigo, J.J.; Calvo-Alvarez, U.; Carreira, J.M.; Garcia-Sanz, M.T.; Muñoz, X.;
Perez-Lopez-Corona, M.P.; Gómez-Conde, M.J.; Casas-Fernández, A.; et al. Blood Eosinophils Could Be Useful as a Biomarker in
Chronic Obstructive Pulmonary Disease Exacerbations. Int. J. Clin. Pract. 2019, 73, 1–7. [CrossRef] [PubMed]
78. Saad, A.B.; Khemakhem, R.; Mhamed, S.C.; Fahem, N.; Migaou, A.; Joobeur, S.; Rouatbi, N. Study of the Role of Blood Eosinophil
Count in Patients with Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease Hospitalized in a Tunisian Center.
Pan Afr. Med. J. 2019, 34, 138. [CrossRef]
79. Lv, M.-Y.; Qiang, L.-X.; Li, Z.-H.; Jin, S.-D. The Lower the Eosinophils, the Stronger the Inflammatory Response? The Relationship
of Different Levels of Eosinophils with the Degree of Inflammation in Acute Exacerbation Chronic Obstructive Pulmonary Disease
(AECOPD). J. Thorac. Dis. 2021, 13, 232–243. [CrossRef] [PubMed]
80. Bélanger, M.; Couillard, S.; Courteau, J.; Larivée, P.; Poder, T.; Carrier, N.; Girard, K.; Vézina, F.-A.; Vanasse, A. Eosinophil
Counts in First COPD Hospitalizations: A Comparison of Health Service Utilization. Int. J. Chron. Obstruct. Pulmon.
Dis. 2018, 13, 3045–3054. [CrossRef]
81. Kolsum, U.; Donaldson, G.C.; Singh, R.; Barker, B.L.; Gupta, V.; George, L.; Webb, A.J.; Thurston, S.; Brookes, A.J.; McHugh, T.D.;
et al. Blood and Sputum Eosinophils in COPD; Relationship with Bacterial Load. Respir. Res. 2017, 18. [CrossRef]
82. Choi, J.; Oh, J.Y.; Lee, Y.S.; Hur, G.Y.; Lee, S.Y.; Shim, J.J.; Kang, K.H.; Min, K.H. The Association between Blood Eosinophil
Percent and Bacterial Infection in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Int. J. COPD 2019, 14, 953–959.
[CrossRef]
83. Wang, F.; Yang, L.; Wang, M.; He, B.; Wei, P.F. Association between Blood Eosinophil Count and Bacterial Infection and Clinical Out-
comes in Patients with Severe Exacerbations of Chronic Obstructive Pulmonary Disease. Chin. Med. J. (Engl.) 2022, 135, 462–464.
[CrossRef]
84. Hills, A.G.; Forsham, P.H.; Finch, C.A. Changes in Circulating Leukocytes Induced by the Administration of Pituitary Adrenocor-
ticotrophic Hormone in Man. Blood 1948, 3, 755–768. [CrossRef]
85. Bass, D.A. Behavior of Eosinophil Leukocytes in Acute Inflammation. II. Eosinophil Dynamics during Acute Inflammation. J.
Clin. Investig. 1975, 56, 870–879. [CrossRef]
86. Lv, J.; Bhatia, M.; Wang, X. Roles of Mitochondrial DNA in Energy Metabolism. In Mitochondrial DNA and Diseases; Sun,
H., Wang, X., Eds.; Advances in Experimental Medicine and Biology; Springer: Singapore, 2017; Volume 1038, pp. 71–83.
ISBN 978-981-10-6673-3.
87. Yousefi, S.; Gold, J.A.; Andina, N.; Lee, J.J.; Kelly, A.M.; Kozlowski, E.; Schmid, I.; Straumann, A.; Reichenbach, J.; Gleich, G.J.;
et al. Catapult-like Release of Mitochondrial DNA by Eosinophils Contributes to Antibacterial Defense. Nat. Med. 2008, 14,
949–953. [CrossRef] [PubMed]
88. Kvarnhammar, A.M.; Cardell, L.O. Pattern-Recognition Receptors in Human Eosinophils. Immunology 2012, 136, 11–20. [CrossRef]
[PubMed]
89. Lehrer, R.I.; Szklarek, D.; Barton, A.; Ganz, T.; Hamann, K.J.; Gleich, G.J. Antibacterial Properties of Eosinophil Major Basic
Protein and Eosinophil Cationic Protein. J. Immunol. 1989, 142, 4428–4434. [PubMed]
90. Giordano, L.; Gregory, A.D.; Pérez Verdaguer, M.; Ware, S.A.; Harvey, H.; DeVallance, E.; Brzoska, T.; Sundd, P.; Zhang, Y.;
Sciurba, F.C.; et al. Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD. Cells 2022,
11, 369. [CrossRef] [PubMed]
91. Szczesny, B.; Marcatti, M.; Ahmad, A.; Montalbano, M.; Brunyánszki, A.; Bibli, S.-I.; Papapetropoulos, A.; Szabo, C. Mitochondrial
DNA Damage and Subsequent Activation of Z-DNA Binding Protein 1 Links Oxidative Stress to Inflammation in Epithelial Cells.
Sci. Rep. 2018, 8, 914. [CrossRef] [PubMed]
92. Avriel, A.; Rozenberg, D.; Raviv, Y.; Heimer, D.; Bar-Shai, A.; Gavish, R.; Sheynin, J.; Douvdevani, A. Prognostic Utility of
Admission Cell-Free DNA Levels in Patients with Chronic Obstructive Pulmonary Disease Exacerbations. Int. J. Chron. Obstruct.
Pulmon. Dis. 2016, 11, 3153–3161. [CrossRef]
93. Yousefi, S.; Mihalache, C.; Kozlowski, E.; Schmid, I.; Simon, H.U. Viable Neutrophils Release Mitochondrial DNA to Form
Neutrophil Extracellular Traps. Cell Death Differ. 2009, 16, 1438–1444. [CrossRef]
94. Martinez-Garcia, M.A.; Miravitlles, M. Bronchiectasis in COPD Patients: More than a Comorbidity? Int. J. COPD
2017, 11, 1401–1411. [CrossRef]
95. Patel, I.S.; Vlahos, I.; Wilkinson, T.M.A.; Lloyd-Owen, S.J.; Donaldson, G.C.; Wilks, M.; Reznek, R.H.; Wedzicha, J.A.
Bronchiectasis, Exacerbation Indices, and Inflammation in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care
Med. 2004, 170, 400–407. [CrossRef]
96. Martínez-García, M.Á.; Soler-Catalunã, J.J.; Sanz, Y.D.; Serra, P.C.; Lerma, M.A.; Vicente, J.B.; Perpiñá-Tordera, M. Factors
Associated with Bronchiectasis in Patients with COPD. Chest 2011, 140, 1130–1137. [CrossRef]
97. Gatheral, T.; Kumar, N.; Sansom, B.; Lai, D.; Nair, A.; Vlahos, I.; Baker, E.H. COPD-Related Bronchiectasis; Independent Impact
on Disease Course and Outcomes. COPD J. Chronic Obstr. Pulm. Dis. 2014, 11, 605–614. [CrossRef] [PubMed]
Toxics 2022, 10, 667 19 of 19

98. Harness-Brumley, C.L.; Elliott, A.C.; Rosenbluth, D.B.; Raghavan, D.; Jain, R. Gender Differences in Outcomes of Patients with
Cystic Fibrosis. J. Womens Health 2014, 23, 1012–1020. [CrossRef]
99. Rosenfeld, M.; Davis, R.; FitzSimmons, S.; Pepe, M.; Ramsey, B. Gender Gap in Cystic Fibrosis Mortality. Am. J. Epidemiol. 1997,
145, 794–803. [CrossRef]
100. Raghavan, D.; Jain, R. Increasing Awareness of Sex Differences in Airway Diseases. Respirology 2016, 21, 449–459. [CrossRef]
[PubMed]
101. Vidaillac, C.; Yong, V.F.L.; Jaggi, T.K.; Soh, M.M.; Chotirmall, S.H. Gender Differences in Bronchiectasis: A Real Issue? Breathe
2018, 14, 108–121. [CrossRef]
102. Capistrano, S.; van Reyk, D.; Chen, H.; Oliver, B. Evidence of Biomass Smoke Exposure as a Causative Factor for the Development
of COPD. Toxics 2017, 5, 36. [CrossRef] [PubMed]
103. Ezzati, M.; Bailis, R.; Kammen, D.M.; Holloway, T.; Price, L.; Cifuentes, L.A.; Barnes, B.; Chaurey, A.; Dhanapala, K.N. Energy
Management and Global Health. Annu. Rev. Environ. Resour. 2004, 29, 383–419. [CrossRef]
104. Silverman, E.K.; Speizer, F.E. Risk Factors for the Development of Chronic Obstructive Pulmonary Disease. Med. Clin. N. Am.
1996, 80, 501–522. [CrossRef]
105. Raherison, C.; Girodet, P.-O. Epidemiology of COPD. Eur. Respir. Rev. 2009, 18, 213–221. [CrossRef]
106. Mannino, D.M.; Buist, A.S. Global Burden of COPD: Risk Factors, Prevalence, and Future Trends. Lancet 2007, 370, 765–773.
[CrossRef]
107. Laniado-Laborín, R. Smoking and Chronic Obstructive Pulmonary Disease (COPD). Parallel Epidemics of the 21 Century. Int. J.
Environ. Res. Public. Health 2009, 6, 209–224. [CrossRef] [PubMed]
108. Cheng, J.; Lu, M.; Sun, H.; Mao, Y. A Survival Analysis of Patients with an Acute Exacerbation of Chronic Obstructive Pulmonary
Disease Discharged from the Respiratory Intensive Care Unit. Ann. Palliat. Med. 2020, 9, 1812–1820. [CrossRef] [PubMed]
109. Gunen, H. Factors Affecting Survival of Hospitalised Patients with COPD. Eur. Respir. J. 2005, 26, 234–241. [CrossRef] [PubMed]
110. Cao, Y.; Xing, Z.; Long, H.; Huang, Y.; Zeng, P.; Janssens, J.-P.; Guo, Y. Predictors of Mortality in COPD Exacerbation Cases
Presenting to the Respiratory Intensive Care Unit. Respir. Res. 2021, 22, 77. [CrossRef] [PubMed]
111. Fruchter, O.; Yigla, M.; Kramer, M.R. D-Dimer as a Prognostic Biomarker for Mortality in Chronic Obstructive Pulmonary Disease
Exacerbation. Am. J. Med. Sci. 2015, 349, 29–35. [CrossRef]
112. Golpe, R.; Mengual-Macenlle, N.; Sanjuán-López, P.; Cano-Jiménez, E.; Castro-Añón, O.; Pérez-de-Llano, L.A. Prognostic Indices
and Mortality Prediction in COPD Caused by Biomass Smoke Exposure. Lung 2015, 193, 497–503. [CrossRef]
113. Bustamante-Fermosel, A.; De Miguel-Yanes, J.M.; Duffort-Falcó, M.; Muñoz, J. Mortality-Related Factors after Hospitalization
for Acute Exacerbation of Chronic Obstructive Pulmonary Disease: The Burden of Clinical Features. Am. J. Emerg. Med.
2007, 25, 515–522. [CrossRef]
114. Carey, M.A.; Card, J.W.; Voltz, J.W.; Arbes, S.J.; Germolec, D.R.; Korach, K.S.; Zeldin, D.C. It’s All about Sex: Gender, Lung
Development and Lung Disease. Trends Endocrinol. Metab. 2007, 18, 308–313. [CrossRef]
115. Chotirmall, S.H. The Microbiological Gender Gap in Cystic Fibrosis. J. Womens Health 2014, 23, 995–996. [CrossRef]
116. Roggenbuck, M.; Anderson, D.; Barfod, K.K.; Feelisch, M.; Geldenhuys, S.; Sørensen, S.J.; Weeden, C.E.; Hart, P.H.; Gorman,
S. Vitamin D and Allergic Airway Disease Shape the Murine Lung Microbiome in a Sex-Specific Manner. Respir. Res. 2016, 17.
[CrossRef]
117. Chamekh, M.; Deny, M.; Romano, M.; Lefèvre, N.; Corazza, F.; Duchateau, J.; Casimir, G. Differential Susceptibility to Infectious
Respiratory Diseases between Males and Females Linked to Sex-Specific Innate Immune Inflammatory Response. Front. Immunol.
2017, 8, 1806. [CrossRef] [PubMed]
118. Casimir, G.J.; Lefèvre, N.; Corazza, F.; Duchateau, J. Sex and Inflammation in Respiratory Diseases: A Clinical Viewpoint. Biol.
Sex Differ. 2013, 4, 16. [CrossRef] [PubMed]
119. Townsend, E.A.; Miller, V.M.; Prakash, Y.S. Sex Differences and Sex Steroids in Lung Health and Disease. Endocr.
Rev. 2012, 33, 1–47. [CrossRef]
120. Fletcher, C.; Peto, R. The Natural History of Chronic Airflow Obstruction. BMJ 1977, 1, 1645–1648. [CrossRef] [PubMed]
121. Vaz Fragoso, C.A.; Gill, T.M. Respiratory Impairment and the Aging Lung: A Novel Paradigm for Assessing Pulmonary Function.
J. Gerontol. A Biol. Sci. Med. Sci. 2012, 67A, 264–275. [CrossRef] [PubMed]
122. Divo, M.J.; Celli, B.R.; Poblador-Plou, B.; Calderón-Larrañaga, A.; de-Torres, J.P.; Gimeno-Feliu, L.A.; Bertó, J.; Zulueta, J.J.;
Casanova, C.; Pinto-Plata, V.M.; et al. Chronic Obstructive Pulmonary Disease (COPD) as a Disease of Early Aging: Evidence
from the EpiChron Cohort. PLoS ONE 2018, 13, e0193143. [CrossRef] [PubMed]
123. MacNee, W. Is Chronic Obstructive Pulmonary Disease an Accelerated Aging Disease? Ann. Am. Thorac. Soc. 2016, 13, S429–S437.
[CrossRef]