Sex differences among inpatients with AECOPD in a tertiary hospital during the COVID-19 pandemic

Abstract

Background

Although sex differences in the characteristics and prognosis of chronic obstructive pulmonary disease (COPD) are well-documented, it is overlooked in the acute exacerbation of COPD (AECOPD). We aimed to examine sex differences among patients with AECOPD who were hospitalized in a tertiary hospital during the pandemic.

Methods

This retrospective study included 199 females and 199 males among 2426 AECOPD patients who were hospitalized between March 2020 and 2022. Characteristics, modified Charlson Comorbidity Index (mCCI) scores, and long-term survival rate were compared based on sex. Associations between sex and variables were analyzed using the Chi-Square test.

Results

Females were older than males (P = 0.02). Females had higher body mass index and pulmonary function test values than males (P = 0.00 for both). GOLD 3, comorbidities, radiological findings, respiratory failure, and biomass exposure were more frequent in females, whereas smoking was more frequent in males (P = 0.00 for all). Among the causes of exacerbations, cardiac events and pneumonia were more frequent in females (P = 0.00 and P = 0.01, respectively), whereas tracheobronchial infections were more frequent in males (P = 0.02). Exacerbations and hospitalizations in the previous year were more prevalent in females than in males (P = 0.00); however, exacerbations during the pandemic were less prevalent (P = 0.00). Hemoglobin, hematocrit, and platelet/lymphocyte levels were higher in males than in females (P = 0.00, P = 0.00, and P = 0.04). Males were more likely than females to have received the BioNTech vaccine (P = 0.02). Compared with males, females had higher mCCI scores and lower 10-year life expectancies (P = 0.00 for both). Females with a COVID-19 history had higher mCCI scores and lower 10-year life expectancies than males with a COVID-19 history (P = 0.00 for both). The long-term survival rate was higher in females than in males (P = 0.04).

Conclusions

The sex-specific characteristics identified in this study may help guide the management of AECOPD in future pandemics.

Background

Chronic obstructive pulmonary disease (COPD) is characterized by persistent symptoms, including dyspnea, cough, and sputum production, along with generally progressive airflow limitation, leading to significant mortality, morbidity, and healthcare costs worldwide [1]. The global prevalence of COPD, estimated at 10.3%, is expected to increase due to the rising prevalence of smoking in low- and middle-income countries and the aging population in high-income countries [2, 3]. Annually, COPD is responsible for approximately three million deaths worldwide [4]. Acute exacerbation of COPD (AECOPD), defined by the sudden worsening of respiratory symptoms, often require additional treatment and is typically triggered by infections (frequently viral) and environmental factors, such as air pollution [5]. These exacerbations contribute to increased rates of hospitalization, readmission, and disease progression. Patients who experience frequent exacerbations (defined as two or more per year) have worse health outcomes and higher morbidity compared with those who experience less frequent exacerbations [6].

Prevention and treatment of exacerbations are critical goals in COPD management. The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presented significant challenges for managing AECOPD. During the pandemic, patients with COPD faced barriers to adequate treatment due to disruptions in the global supply chain, economic hardships that limited their ability to afford medications, and the diversion of drugs to treat COVID-19 patients without COPD [7]. Although AECOPD admissions significantly decreased during the pandemic, the overall severity of exacerbations and mortality rates remained unchanged [8].

Although males historically had a higher prevalence of COPD compared to females, the gap has been narrowing in recent decades due to the rise in smoking among females [9]. Several studies have reported sex-related differences in predisposing factors and effects, disease onset, clinical presentations, and outcomes, highlighting the significance of the sex phenotype in COPD [10]. An association between male sex and smoke particles in AECOPD, while an association between female sex and air pollution exposure were indicated [11]. Smoker females are more prone to severe COPD at an earlier age than males due to their more vulnerability to smoking [12]. Martinez et al. reported that among patients with severe COPD, females tend to have more airway disease, and males have more emphysema [13]. Buist et al. demonstrated that females experience more dyspnea and have a higher frequency of exacerbations than males [14]. However, there remains a lack of literature regarding sex differences in patients with AECOPD; This issue also was overlooked during the pandemic.

Our study aimed to identify sex differences in demographic, clinical, radiological, and laboratory characteristics, as well as the use of home respiratory support devices, comorbidities, COVID-19 and vaccination histories, modified Charlson Comorbidity Index (mCCI) scores, and long-term survival among inpatients with AECOPD during the pandemic.

Materials and methods

This retrospective cross-sectional study was conducted at a reference pulmonology center designated as a COVID-19 hospital by the Turkish Ministry of Health during the pandemic.

Patient recruitment

Overall, 2,426 patients with AECOPD who were hospitalized initially in chest disease clinics during the pandemic (March 2020–2022) were identified using the Hospital Registration System. Among total patients, 920 patients were female, and 1506 patients were male. Of the scanned 354 female and 425 male patients, 199 patients each were included in the study (Fig. 1).

Fig. 1.

Flowchart of the patient recruitment

Data collection

Data regarding the initial hospitalizations of patients during the pandemic were obtained from the hospital’s electronic database. Comparisons were made between female and male patients.

Data were recorded concerning patient age, sex, body mass index (BMI), pulmonary function test parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio], Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades (1–4), chronic use of respiratory support devices [nebulizer, oxygen concentrator, nebulizer + oxygen concentrator, nebulizer + oxygen concentrator + bilevel positive airway pressure], participation in pulmonary rehabilitation, and thoracic computed tomography findings (emphysema, bronchiectasis, and emphysema + bronchiectasis). Additionally, the causes of exacerbation (tracheobronchial infection, pneumonia, COVID-19, pneumothorax, pulmonary embolism, cardiac and metabolic causes, and non-compliance with treatment), the presence and type of respiratory failure [hypoxemic (type 1) and hypercapnic (type 2)], and values of admission laboratory tests, including complete blood counts and arterial blood gases, were recorded. Data on exacerbation and hospitalization counts in the previous year, as well as exacerbation counts after the first hospitalization during the pandemic, comorbidities, smoking status (former smoker, current smoker, or nonsmoker), and biomass exposure, which had been recorded through questioning patients and their companions, were obtained from the electronic reports.

Data were also collected regarding COVID-19 histories, including the number of COVID-19 infections during the pandemic, the number of patients with real-time polymerase chain reaction (RT-PCR)-positive COVID-19, the number of patients with RT-PCR-negative COVID-19, vaccination status, and vaccine type (Sinovac, BioNTech, and Turkovac).

Survival status was obtained from the national death notification system as of February 2024. mCCI scores and the expected 10-year survival percentage were calculated separately for the entire cohort and for patients who experienced COVID-19.

Definitions

COPD

Patients had been diagnosed with COPD based on forced spirometry, which demonstrated a post-bronchodilator FEV1/FVC < 0.7 after the administration of 400 mcg of salbutamol [15].

AECOPD

An exacerbation of COPD was defined as a worsening of dyspnea, cough, and sputum production occurring within a period of less than 14 days [16].

Measures

Pulmonary function test (PFT)

PFT had been conducted using a Jaeger Master scope PC spirometer. PFT values from within one year before the pandemic were assessed.

GOLD grades

The severity of airflow obstruction in COPD patients was assessed using the post-bronchodilator FEV1 value as a percentage of the predicted value and was staged following the 2024 GOLD report [15].

Modified Charlson Comorbidity Index (mCCI)

This index was used to predict the 10-year mortality risk for a patient based on age and nine comorbid conditions [17].

Statistical analysis

Data analysis was conducted using SPSS software (version 25.0; IBM Corp., Armonk, NY, USA). Normality of the data was assessed by examining the skewness and kurtosis values of the variables. If these values were within two standard deviations, the data were considered to follow a normal distribution. The Chi-square independence test was used to evaluate associations between sex and categorical variables. For continuous variables, the independent samples t-test was applied to those meeting the normality assumption, whereas the Mann-Whitney U test was used for variables that did not meet this assumption. A value of P < 0.05 was accepted as statistically significant.

Results

The average ages for females and males were 68.28 ± 11.28 and 65.79 ± 9.54 years, respectively; and their average BMIs were 29.16 ± 8.57 kg/m² and 25.10 ± 4.97 kg/m². Mean values for age, BMI, FEV1, and FEV1/FVC were higher in females (P = 0.02, P = 0.00, P = 0.00, and P = 0.00, respectively). Smoking was more prevalent among males (N = 194 vs. N = 122, P = 0.00), whereas females had a greater exposure to biomass (N = 127 vs. N = 58, P = 0.00). The number of current smokers was similar among females and males (N = 64 vs. N = 83). The GOLD grade-3 category comprised more females than males (P = 0.00) (Table 1).

Table 1.

Demographics, pulmonary function test results, severity of airway obstruction, respiratory supportive treatment, and radiological findings of the study patients based on sex

Variable	Females		Males		P
	N	Mean ± SD	N	Mean ± SD
Age	199	68.28 ± 11.28	199	65.79 ± 9.54	0.02*
BMI (body mass index) kg/m2	190	29.16 ± 8.57	190	25.10 ± 4.97	0.00*
PFT parameters (%)
FEV1 (≥ 80%) †	118	45.89 ± 16.86	132	39.44 ± 16.17	0.00*
FVC (≥ 80%)	118	53.48 ± 19.15	132	51.42 ± 15.61	0.35
FEV1/FVC (≥ 70%)	118	67.10 ± 14.45	132	57.17 ± 13.41	0.00*

	N	%	N	%
Smoking status (N = 398)
Nonsmoker	77	19.3	5	1.3	0.00*
Current smoker	64	16.1	85	21.4
Former smoker	58	14.6	109	27.4
Total	199	50	199	50
Biomass exposure (N = 398)
No	72	18.1	141	35.4	0.00*
Yes	127	31.9	58	14.6
Total	199	50	199	50
GOLD grades (N = 246)
Grade 1	4	1.6	9	3.7	0.00*
Grade 2	39	15.9	21	8.5
Grade 3	56	22.8	44	17.9
Grade 4	19	7.7	54	22
Total	118	48	128	52
Home respiratory support devices (N = 398)
No	90	22.6	86	21.6	0.69
Yes	109	27.4	113	28.4
Total	199	50	199	50
Nebulizer
No	163	41	171	43	0.28
Yes	36	9	28	7
Nebulizer + Oxygen concentrator
No	177	44.5	164	41.2	0.06
Yes	22	5.5	35	8.8
Nebulizer + Oxygen concentrator + BIPAP
No	151	37.9	157	39.4	0.47
Yes	48	12.1	42	10.6
Oxygen concentrator
No	196	49.2	193	48.5	0.50
Yes	3	0.8	6	1.5
CPAP
No	196	49.2	199	50	-
Yes	3	0.8	0	0
Pulmonary rehabilitation (N = 398)
No	137	34.4	127	31.9	0.29
Yes	62	15.6	72	18.1
Total	199	50	199	50
CT findings (N = 398)
No	0	0	44	11.1	0.00*
Yes	199	50	155	38.9
Total	199	50	199	50
Emphysema
No	44	11.1	110	27.6	0.00*
Yes	155	38.9	89	22.4
Bronchiectasis
No	101	25.4	172	43.2	0.00*
Yes	98	24.6	27	6.8
Emphysema + bronchiectasis
No	198	49.7	160	40.2	0.00*
Yes	1	0.3	39	9.8

N number of patients, SD standard deviation, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, GOLD grades Global initiative for chronic Obstructive Lung Disease grades, severity of airway obstruction, PFT pulmonary function test, BIPAP bi-level positive airway pressure, CPAP continuous positive airway pressure, CT computed tomography

† Standard values of PFT parameters in parenthesis

*P < 0.05, significant value

Females had more frequent radiological findings than males (P = 0.00). Specifically, emphysema and bronchiectasis were significantly more frequent in females (P = 0.00 for both). However, the combination of emphysema and bronchiectasis was more frequent in males (P = 0.00) (Table 1).

Among the causes of exacerbations, cardiac events and pneumonia led to more frequent exacerbations in females than in males (P = 0.00 and P = 0.01, respectively), whereas tracheobronchial infections caused more frequent exacerbations in males (P = 0.02). Females also experienced respiratory failure more frequently than males (P = 0.00); type 1 respiratory failure was more frequent among females (P = 0.00). While females had a higher prevalence of exacerbations and hospitalizations in the year prior (P = 0.00), they had fewer exacerbations during the pandemic after initial hospitalization (P = 0.00) (Table 2).

Table 2.

Comparison of initial hospitalization information between female and male patients with AECOPD during the COVID-19 pandemic period

Variable	Females		Males		P
	N	%	N	%
Etiology of exacerbation (N = 398)
Tracheobronchial infection
No	160	40.2	139	34.9	0.02*
Yes	39	9.8	60	15.1
Pneumonia
No	107	27	133	33.5	0.01*
Yes	92	23.2	66	16.6
COVID-19
No	173	43.5	176	44.2	0.76
Yes	26	6.5	23	5.8
Pneumothorax
No	198	49.7	195	49	-
Yes	1	0.3	4	1
Pulmonary embolism
No	188	47.2	195	49	0.11
Yes	11	2.8	4	1
Cardiac events
No	149	37.4	194	48.7	0.00*
Yes	50	12.6	5	1.3
Metabolic causes
No	190	47.7	197	49.5	0.07
Yes	9	2.3	2	0.5
Lack of treatment compliance
No	176	44.2	164	41.2	0.09
Yes	23	5.8	35	8.8
Respiratory failure (N = 398)
No	5	1.3	34	8.5	0.00*
Yes	194	48.7	165	41.5
Type of respiratory failure (N = 359)
Type 1	132	36.8	82	22.8	0.00*
Type 2	62	17.3	83	23.1
Total	194	54	165	46

	N	Mean ± SD	N	Mean ± SD
Exacerbation count in the previous year	199	1.90 ± 1.91	199	0.78 ± 1.77	0.00*
Hospitalization counts in the previous year	199	0.35 ± 0.66	199	0.16 ± 0.64	0.00*
Exacerbation count during the pandemic following the initial hospitalization	88	1.25 ± 2.02	199	2.33 ± 3.74	0.00*

N number of patients, % percentage of patients, Type 1 hypoxemic respiratory failure, Type 2 hypercapnic respiratory failure, SD standard deviation 

*P < 0.05, significant value

Females had higher glucose, albumin, and calcium levels than males (P = 0.01 for all). In contrast, their creatinine, estimated glomerular filtration rate (eGFR), gamma-glutamyl transferase (GGT), and C-reactive protein (CRP) values were lower (P = 0.02, P = 0.00, P = 0.03, and P = 0.02, respectively). Females had lower hemoglobin, hematocrit, and platelet-to-lymphocyte (PLT/LYM) ratios than males (P = 0.00, P = 0.00, and P = 0.04) (Table 3).

Table 3.

Admission laboratory findings of the study patients according to sex

Variable	Females		Males		P
	N	Mean ± SD	N	Mean ± SD
Glucose (70–115 mg/dl) †	199	150.25 ± 65.53	198	137.54 ± 58.93	0.01*
BUN (17–43 mg/dl)	199	44.13 ± 28.82	199	43.74 ± 25.55	0.30
Creatinine (0.6–1.45 mg/dl)	199	0.90 ± 0.54	199	0.92 ± 0.52	0.02*
Albumin (35–53 g/L)	199	37.32 ± 4.73	199	36.07 ± 5.07	0.01*
Uric acid (2.5–7.2 mg/dl)	92	5.76 ± 4.43	44	5.29 ± 2.28	0.82
EGFR (70–140 ml/dk/1.73 m2)	199	76.55 ± 26.63	198	87.99 ± 23.06	0.00*
AST (< 35 U/L)	198	26.41 ± 22.84	198	27.99 ± 21.61	0.34
ALT (< 45 U/L)	198	21.93 ± 22.00	199	25.57 ± 33.19	0.68
LDH (< 247 U/L)	193	293.39 ± 130.83	195	302.79 ± 248.22	0.82
GGT (< 80 U/L)	191	38.89 ± 77.88	189	43.92 ± 59.96	0.03*
Total bilirubin (0-1.2 mg/dl)	197	0.64 ± 2.05	199	0.54 ± 0.48	0.10
APTT (24–36 s)	186	28.70 ± 5.43	193	29.71 ± 5.60	0.08
PT (14.1 s)	187	14.24 ± 4.65	194	14.15 ± 4.40	0.97
D-dimer (0-0.5 mg/L)	130	1.19 ± 1.88	78	1.29 ± 1.98	0.30
CRP (< 5 mg/L)	199	54.47 ± 72.42	197	77.84 ± 88.03	0.02*
Procalcitonin (< 0.1 ng/ml)	183	0.22 ± 0.65	178	0.93 ± 6.02	0.19
Na (133–150 mmol/L)	199	136.60 ± 4.29	199	136.98 ± 4.47	0.53
K (3.3–5.5 mmol/L)	198	4.47 ± 0.64	198	4.53 ± 0.61	0.45
Cl (98–107 mmol/L)	199	97.75 ± 5.35	193	97.79 ± 5.18	0.94
Ca (8.6–10.6 mg/dl)	199	8.95 ± 0.64	191	8.78 ± 0.59	0.01*
ABG parameters
pH (7.35–7.45)	187	7.40 ± 0.07	173	7.41 ± 0.06	0.74
pO2 (70–100 mmHg)	187	63.36 ± 30.07	173	58.00 ± 12.93	0.44
pCO2 (32–45 mmHg)	187	49.69 ± 14.46	173	48.92 ± 14.27	0.61
SatO2 (%95.4)	187	86.73 ± 9.60	173	87.55 ± 9.37	0.54
WBC (4–10 10e3/Ul)	199	10.89 ± 5.13	199	11.57 ± 5.44	0.15
Hb (11–16 g/dl)	199	12.36 ± 2.09	199	13.37 ± 2.34	0.00*
HTC (37–54%)	199	39.15 ± 6.34	199	41.72 ± 6.98	0.00*
Neutrophil (2–7 10e3/Ul)	199	8.46 ± 4.77	199	9.02 ± 5.01	0.25
Eosinophil (0.02–0.5 10e3/Ul)	199	0.15 ± 0.21	199	0.18 ± 0.40	0.45
Platelet (150–450 10e3/Ul)	199	276.11 ± 100.07	199	272.45 ± 103.46	0.50
Lymphocyte (0.8-4 10e3/Ul)	199	1.58 ± 1.00	199	1.43 ± 0.80	0.19
NEU/LYM	199	7.88 ± 8.40	199	9.71 ± 10.41	0.08
EOS/LYM	199	0.09 ± 0.14	199	0.13 ± 0.31	0.59
PLT/LYM	199	219.90 ± 163.01	199	274.80 ± 252.98	0.04*

N number of patients, SD standard deviation, BUN blood urea nitrogen, EGFR estimated glomerular filtration rate, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, GGT gamma-glutamyl transferase, APTT activated partial thromboplastin time, PT prothrombin time, CRP C-reactive protein, Na sodium, K potassium, CL chlorine, Ca calcium, ABG arterial blood gases, pH power of Hydrogen, pO2 partial oxygen pressure, pCO2 partial carbon dioxide pressure, SatO2 arterial oxygen saturation, WBC White blood cell, Hb hemoglobin, HTC hematocrit, NEU neutrophil, LYM lymphocyte, EOS eosinophil, PLT platelet

†Standard values in parenthesis

*P < 0.05, significant value

Overall, 20.9% of females and 16.8% of males had a history of COVID-19. Among these, 19.1% of females and 16.1% of males tested positive for COVID-19 via RT-PCR, whereas 3.4% of females and 2.5% of males tested negative. Regarding vaccination, 46.7% of females received the COVID-19 vaccine compared with 33.3% of males. A significant difference was noted in the use of the BioNTech vaccine, which was administered more frequently to males than to females (P = 0.02) (Table 4).

Table 4.

COVID-19 information of the study patients based on sex

Variable	Females		Males		P
	N	%	N	%
COVID-19 history (N = 398)
No	116	29.1	132	33.2	0.10
Yes	83	20.9	67	16.8
Total	199	50	199	50
Count of COVID-19 infections during the pandemic (N = 398)
None	116	29.1	132	33.2	0.21
1	62	15.6	47	11.8
≥ 2	21	5.3	20	5
Total	199	50	199	50
RT-PCR (+) COVID-19 (N = 398)
No	123	30.9	135	33.9	0.21
Yes	76	19.1	64	16.1
Total	199	50	199	50
RT-PCR (-) COVID-19 (N = 204)
No	192	94.1	0	0	-
Yes	7	3.4	5	2.5
Total	199	97.5	5	2.5
COVID-19 vaccination (N = 105)
No	13	12.4	8	7.6	0.96
Yes	49	46.7	35	33.3
Total	62	59	43	41

Type of COVID-19 vaccine	N	Mean ± SD	N	Mean ± SD
Turkovac	22	0.05 ± 0.21	35	0.09 ± 0.37	0.83
Sinovac	62	1.27 ± 1.37	35	1.69 ± 1.23	0.14
BioNTech	62	1.10 ± 1.24	35	1.71 ± 1.23	0.02*

N number of patients, % percentage of patients, RT-PCR real-time polymerase chain reaction, COVID-19 coronavirus disease 2019, SD standard deviation

*P < 0.05, significant value

The number of comorbidities was higher in females than in males (P = 0.00). Among these comorbidities, females had higher rates of coronary artery disease (CAD), congestive heart failure (CHF), peripheral vascular disease, cerebrovascular accident (CVA), dementia, ulcers, diabetes mellitus (DM), chronic kidney disease (CKD), obstructive sleep apnea syndrome (OSAS), and asthma than males (P = 0.00 for all except cerebrovascular accident and dementia, where P = 0.04 and P = 0.01, respectively) (Table 5).

Table 5.

Comorbidities of the study patients according to sex

Variable Number of comorbidities	Females		Males		P 0.00*
	N	Mean ± SD	N	Mean ± SD
	199	2.99 ± 1.83	199	0.77 ± 0.88
	N	%	N	%
Comorbidities (n = 398)
CAD
No	78	19.6	153	38.4	0.00*
Yes	121	30.4	46	11.6
CHF
No	98	24.6	171	43.0	0.00*
Yes	101	25.4	28	7
Peripheral vascular diseases
No	177	44.5	199	50	0.00*
Yes	22	5.5	0	0
CVA
No	189	47.5	197	49.5	0.04*
Yes	10	2.5	2	0.5
Dementia
No	185	46.5	196	49.2	0.01*
Yes	14	3.5	3	0.8
Connective tissue disease
No	196	49.2	196	49.2	0.66
Yes	3	0.8	3	0.8
Peptic ulcer
No	159	39.9	199	50	0.00*
Yes	40	10.1	0	0
Liver Disease
No	199	50.0	197	49.5	0.25
Yes	0	0	2	0.5
DM
No	105	26.4	170	42.7	0.00*
Yes	94	23.6	29	7.3
CKD
No	164	41.2	190	47.7	0.00*
Yes	35	8.8	9	2.3
Solid tumor
No	184	46.2	177	44.5	0.30
Yes	15	3.8	22	5.5
Leukemia
No	197	49.5	199	50	0.25
Yes	2	0.5	0	0
OSAS
No	169	42.5	194	48.7	0.00*
Yes	30	7.5	5	1.3
Asthma
No	111	27.9	194	48.7	0.00*
Yes	88	22.1	5	1.3

N number of patients, % percentage of patients, SD standard deviation, CAD coronary artery disease, CHF congestive heart failure, CVA cerebrovascular accident, DM diabetes mellitus, CKD chronic kidney diseases, OSAS obstructive sleep apnea syndrome

*P < 0.05, significant value

The long-term survival rate was higher for females than for males (26.4% vs. 21.1%, P = 0.04). Females had higher mCCI values than males, and their expected 10-year survival rates were lower than those of males (P = 0.00 for both). Among patients with a history of COVID-19, no significant association was detected between long-term survival rates and sex (P = 0.76), and females had a higher mCCI value and a lower expected 10-year survival rate than males (P = 0.00 for both) (Table 6).

Table 6.

Comparison of long-term survival rates, modified Charlson Comorbidity Index scores, and expected 10-year survival rates by sex among total patients and patients who experienced COVID-19

	Females		Males		P
	N	%	N	%
Survival status of total patients (N:398)
Survivor	115	28.9	94	23.6	0.04*
Non-survivor	84	21.1	105	26.4
Survival status of patients with COVID-19 history (N:150) Survivor Non-survivor	43 40	28.7 26.7	33 34	22.0 22.7	0.76

	N	Mean ± SD	N	Mean ± SD
mCCI scores of total patients	199	5.48 ± 2.17	199	4.37 ± 2.37	0.00*
Expected 10-year survival of total patients (%)	199	27.18 ± 33.10	199	48.09 ± 33.75	0.00*
mCCI scores of patients with COVID-19 history	83	5.61 ± 2.0	67	4.72 ± 2.52	0.00*
Expected 10-year survival of patients with COVID-19 history (%)	83	22.81 ± 32.07	67	40.79 ± 33.84	0.00*

N number of patients, % percentage of patients, SD standard deviation, mCCI modified Charlson Comorbidity Index, COVID-19 coronavirus disease 2019

*P < 0.05, significant value

Discussion

The present study analyzed differences between female and male COPD patients upon their initial hospitalization at a reference pulmonology center for exacerbation during the pandemic. Consistent with previous studies, females with COPD had higher BMIs than males in this study [18, 19]. However, a study reported that females with COPD had a lower BMI than males [20]. This discrepancy in BMI may be attributed to variations in factors such as race, ethnicity, age, and the presence of metabolic syndrome (MetS). A study including a population similar to this study’s participants, primarily elderly individuals, found a higher prevalence of BMI-related obesity in females. Steroid sex hormones, genetic factors, and physical inactivity may be responsible for the increased susceptibility of females to obesity with aging [21]. Postmenopausal estrogen deficiency affects the activity of diacylglycerol acyltransferase and acyl-CoA synthetase, leading to increased fatty acid storage in subcutaneous adipose tissue [22]. An in vitro study using human cells demonstrated that testosterone has inverse effects on BMI levels, including increasing lipolysis, reducing lipid accumulation, and inhibiting the adipogenic differentiation of human mesenchymal stem cells and preadipocytes through an androgen receptor-dependent mechanism [23].

Smoking remains the primary predisposing factor for COPD. Due to declining tobacco use in Europe, the tobacco industry has shifted its focus to women and youth in developing nations for market expansion [24]. Consequently, despite stringent tobacco control measures in Türkiye since 2004, cigarette smoking rates have increased from 12.6% to 39.2% in females and males, respectively, in 2012, to 19.6% and 41.9% in 2022 [25, 26]. Notably, the higher increase in smoking rates among females may explain the narrowing of the current smoker gap between females and males (N = 64 vs. N = 85) observed in this study. Even now, according to the most recent 2022 Turkish smoking prevalence statistics, the prevalence of male smokers is 2-fold higher than that of female smokers. This study supported the statistics, as male nonsmokers were less frequent than female nonsmokers (N = 5 vs. N = 77) [26]. Conversely, biomass exposure, a non-smoking risk factor for COPD, was more prevalent among females, consistent with a previous study from a Turkish rural area [27].

Females had higher FEV1 and FEV1/FVC values relative to males, consistent with a previous study [18]. This finding also aligns with the results in several studies of stable COPD patients [28, 29]. Although females had better PFT values and lower smoking prevalence, they experienced more exacerbations and hospitalizations in the previous year. Additionally, severe airway obstruction (GOLD 3), respiratory failure, and type 1 respiratory failure were more frequent in females than males. The discrepancies between laboratory results and clinical manifestations may be attributed to the higher prevalence of asthma, OSAS, DM, and CHF in females, observed in this study and previous studies [19, 30, 31]. Furthermore, the effects of smoking appear to be more detrimental in females, leading to more rapid lung function decline [32]. Cardiac events, pneumonia, and anemia, which were more frequent in females, likely contributed to higher rates of hypoxia compared with males. Additionally, the overlap syndromes of OSAS-COPD and asthma-COPD were more frequent in females, potentially exacerbating airway obstruction.

Males experienced more exacerbations after their initial hospitalization with AECOPD during the pandemic, a finding that contrasts with the lower incidence of COVID-19 in males than in females. This discrepancy may be explained by the higher prevalence of tracheobronchial infections in males, which was a more frequent cause of exacerbation compared to females. Males may have experienced more co-infections or superinfections with other pathogens after the first exacerbation during the pandemic. The greater susceptibility of males to lower respiratory tract infections and viral infections supports this hypothesis [33, 34].

Consistent with previous studies, bronchiectasis was more appeared in females than in males in the present study [19, 30]. However, some studies have revealed a higher prevalence of bronchiectasis in males with COPD [35, 36]. Intriguingly, emphysema was more frequently detected in females, contrary to the results of several studies [19, 35]. Bronchiectasis combined with emphysema was more prevalent in males. These differences in radiological findings may be attributed to variations in the study populations, including differences in steroid sex hormones, genetic factors (i.e., α-1 antitrypsin deficiency [AATD]), indoor biomass exposure, smoking patterns, and morbidity history (i.e., tuberculous sequelae). Sex differences in bronchiectasis may be largely attributed to the type, primarily pattern, and concentration of sex steroid hormones, which vary throughout life and between the sexes. Additionally, microbiology and host immunity are important issues affected by sex in the development of bronchiectasis [37]. AATD, the first genetic determinant of the disease to be validated by functional evidence, is the most well-established genetic etiology of COPD. Females with AATD experience more respiratory exacerbations and develop emphysema at lower tobacco exposure levels [38, 39]. In line with the literature, this study revealed that although females smoked less than males, they had more emphysema and experienced more frequent exacerbations in the previous year. AATD may be a contributing factor to the mentioned outcomes.

This study is the first to explore sex differences in COVID-19 findings among patients with AECOPD hospitalized during the pandemic. Females had a slightly higher incidence of COVID-19 than males (N = 83 vs. N = 67), with more RT-PCR-positive cases (N = 76 vs. N = 64) and more RT-PCR-negative cases (N = 7 vs. N = 5). Males were significantly more likely to have received the BioNTech vaccine, likely due to the policy mandating vaccination for employees during the pandemic—a reflection of the more active role males typically play in the workforce in Türkiye. Although vaccination rates were marginally higher in females, the slightly higher occurrence of COVID-19 in females than in males suggests that the BioNTech vaccine contributed to more effective COVID-19 prevention. This hypothesis is supported by previous studies indicating that the BioNTech vaccine is associated with a lower risk of COVID-19 infection and reduced severity of symptoms in adults [40]. Additionally, the higher prevalence of immunosuppressive conditions, such as DM, CHF, CKD, CVA, dementia, and anemia, could have contributed to the increased frailties in females.

In terms of laboratory findings, females had higher glucose, albumin, and calcium levels than males. MetS is a cluster of conditions including dyslipidemia, diabetes mellitus, abdominal obesity, and high blood pressure. MetS increases the risks of vascular and neurological disorders, insulin resistance, DM, and atherosclerotic heart diseases [41]. In this sense, in this study, which primarily included elderly patients, we consider that females were more prone to MetS than males due to higher BMI, glucose, and albumin levels, and lower eGFR. Similarly, Yi et al. reported that the prevalence of MetS was higher in older females than in young adults, as compared to males [42]. We suggest that steroid sex hormones have an impact on this issue. MetS has a reverse association with sex hormone binding globulin (SHBG), estrogen, and testosterone levels. Menopause, where SHBG levels decline significantly compared to estrogen levels and testosterone remains at the same level, is a predisposing factor for MetS, regardless of age [43]. Higher serum calcium levels in females may result from biological and behavioral differences. Minisola et al. indicated that serum calcium levels decreased with aging in males, associated with fluctuating parathyroid hormone levels and altered phosphate metabolism [44]. Alquaiz et al. reported that vitamin D deficiency, which can reduce calcium absorption, was more prevalent in males and was associated with dietary habits, central obesity, and underuse of vitamin D supplements [45].

Among laboratory results, CRP, GGT, eGFR, and creatinine levels were found lower in females than in males. The lower eGFR in females was correlated with a higher prevalence of CKD in females. Among the causes of exacerbation, pneumonia was more frequent in females, in contrast with the previous literature [46]. We suggest that this outcome was due to the fact that females were older and had more comorbidities than males. Among causes for exacerbations, despite women having a greater age and comorbidity burden, females and males experienced similar rates of COVID-19 infection (N = 26 vs. N = 23), and males experienced more tracheobronchial infections. Differences in steroid sex hormones and genetic factors may contribute to the susceptibility of males to these infections. Estrogens at physiological concentrations are considered to have an immune-stimulating function by upregulating cellular and humoral immunity [47]. The X chromosome encodes a large number of genes with immunomodulatory functions, one of which is the TLR7 gene [48]. TLR7 expression levels and, consequently, immune sensing of RNA antigens (i.e., virus vaccines and self-antigens) are more potent in females [49, 50]. Inverse TLR7 mutations, which are unique to males, have been associated with susceptibility to viral infections, such as SARS-CoV-2 [51]. The infections have the potential to elevate CRP levels, and it is likely that the increase in CRP was more pronounced in males due to these infections. The fact that the CRP elevation, which indicates the inflammatory response, was higher in males may be due to the anti-inflammatory effect of androgens [47].

Consistent with previous findings, females were also more anemic than males [18, 52]. Among the complete blood indices, only the PLT/LYM was significantly lower in females. The PLT/LYM ratio is an independent predictor of exacerbations within a year in stable COPD patients [53]. This finding aligns with the observation that females had a lower PLT/LYM ratio and fewer exacerbations during the pandemic than males in this study.

Literature on the sex differences in survival rates of patients with AECOPD are limited. A review study demonstrated that male sex was a risk factor for short-term mortality in AECOPD [54]. Zhang et al. reported that female smokers with AECOPD had a higher in-hospital mortality than male smokers, and male smokers had a higher 3-year mortality than female smokers [55]. Similarly, females exhibited a higher long-term survival rate than males in this study. However, sex had no impact on long-term survival rate in patients with a history of COVID-19, which might be due to the small sample size. Interestingly, among total patients and those who experienced COVID-19, females had a higher mCCI score and a lower 10-year life expectancy than males. We assume that sex differences in the prognosis and mortality risks of comorbidities such as DM and complications, cardiovascular diseases (CVD), and solid tumors played roles in this contrast. Previous studies have highlighted DM, CVD, and depression are the significant comorbidities causing high mortality in patients with COPD [31, 56]. A study showed that while CVD and DM were more prevalent in males with COPD than in females, the risks associated with these comorbidities differed by sex. Specifically, CVD was linked to a higher risk of mortality in females, whereas DM was associated with a higher risk of mortality in males [31]. In line with this study, despite a higher prevalence of mortal comorbidities such as CVD, DM, CKD, and dementia in females, females survived longer than males. The pandemic has resulted in increased morbidity and mortality by delaying hospital admissions for cancer patients and causing disruptions in their diagnosis, management, and treatment [57]. The pandemic period, during which the survival analysis was conducted, was another confounder that reduced the long-term survival rate of male patients with a higher frequency of solid tumors. On the other hand, the mCCI measures 10-year mortality. Nevertheless, we analyzed mortality over a maximum of four years, which might have led to an underestimation of the mortality rates. We consider that the fact that female patients were older and had more comorbidities influenced the mCCI results.

This study has some limitations. The major limitation is its retrospective design, which results in missing data. The study could have been more comprehensive if missing data, such as symptoms, chronic medications, and broader biochemistry results (including lipids, cholesterol, and vitamin D levels), as well as genetic markers (such as AAT), had been available. Another limitation is that the study was conducted at a single center. However, the strength of the study lies in its setting: one of the country’s key reference pulmonology centers, which was designated as a COVID-19 hospital during the pandemic and specialized in pulmonary diseases like COPD. These features of the center ensured that incorrect hospitalizations of patients presenting with AECOPD to the emergency department were excluded; patient information was recorded accurately and comprehensively.

In summary, we identified significant differences between females and males upon their initial hospitalizations with AECOPD during the pandemic. These differences included demographics, COPD risk factors, PFT results, severity of airway obstruction, radiological characteristics, admission laboratory results, exacerbation causes, respiratory failure, exacerbation and hospitalization count in the previous year, exacerbation count during the pandemic after the initial hospitalization, type of COVID-19 vaccine, comorbidities, mCCI scores, and long-term and expected 10-year survival rates. Our findings may guide physicians in the clinical management and treatment of patients with AECOPD during pandemics. The observed sex-related differences underscore the need for physicians to create timely care plans for AECOPD, with a focus on raising individual patient awareness of the disease. Additionally, these differences provide valuable insights for the long-term follow-up of AECOPD patients after discharge. However, multicenter studies are required to further explore this issue.

Authors’ contributions

HA contributed to the design and project administration of the study, the analysis and interpretation of the data and the writing of the manuscript. NSV contributed to the analysis and interpretation of the data. All authors contributed to the critical review and final approval of the manuscript for publication.

Funding

The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study received approval from the local Ethics Committee of Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital (approval no. 2023 − 382; dated October 8, 2023) and was conducted in accordance with the Declaration of Helsinki. Informed consent from the study participants was no required due to retrospective design of the study.

Consent for publication

Not required due to retrospective design of the study.

Competing interests

The authors declare no competing interests.