Introduction

Chronic obstructive pulmonary disease (COPD) is a common disease that lowers the quality of life of sufferers and their families and imposes a heavy economic burden on society. According to data derived from the World Health Organization (WHO) in 2019, COPD is currently the third leading cause of death worldwide1. On average, each COPD patient suffers from 0.5 to 3.5 episodes of acute exacerbations per year, and AECOPD is a major cause of death and causes huge medical expenditures2.

An acute pulmonary exacerbation includes flaring up or worsening of the signs and symptoms such as cough, excessive mucus, and dyspnea. However, some studies have suggested that the clinical presentation is manifested differently in women compared with men. A study has found that young female COPD patients tend to exhibit more severe symptoms of breathlessness and airflow blockage, a higher risk of acute exacerbation, and the GOLD group was more divided into group B and group D3. Among comorbidities, cardiometabolic diseases such as osteoporosis is more prevalent in women, male patients are subjected to a greater rate of cardiovascular disease, such as hypertension, ischemic heart disease, chronic heart failure, etc.3. With respect to the treatment, female patients was associated with the risk of COPD hospitalization, and had higher daily medications4. However, the prognosis research of COPD varies widely. A real-world study showed that the mortality of COPD is around 11.2% and 10.8% in men and women over a period of 3 years, the results did not display significant differences5. Tamara et al. found that COPD-attributed mortality was worse in males (76.3%) than in females (86.9%) over a period of 5 years (P < 0.001)6.

While these statistics provide some evidence of the difference in women compared with men, these data are incomplete, and related research on COPD is relatively scarce in China. Therefore, the study was aimed at describing the clinical characteristics of and the outcomes of AECOPD patients between different sex to help provide a better understanding of the population and identify certain features that may drive individualized therapy.

Methods

Study population

This study is a retrospective cohort study aimed at investigating the differences between male and female COPD patients. We retrospectively enrolled 352 inpatients with a diagnosis of AECOPD in our hospital between 1 January 2019 to 31 December 2021 from the general ward and intensive care unit in the hole hospital. Pulmonary function tests that meet the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 COPD diagnostic criteria7, all methods were performed in accordance with the relevant guidelines and regulations; diagnosis of COPD was defined by the presence of a postbronchodilator FEV1/FVC < 0.70 in patients with appropriate symptoms and significant exposure to noxious stimuli, according to the GOLD 2019 report; AECOPD were defined as an acute worsening of respiratory symptoms that results in additional therapy and requires hospitalization or visiting the emergency department. Chronic pulmonary heart disease is defined as right ventricular enlargement/dysfunction that develops as a consequence of pulmonary hypertension, which is secondary to chronic respiratory diseases, primarily COPD in our study population. It is characterized by right ventricular hypertrophy and potential right heart failure due to increased pulmonary vascular resistance. Criteria for admission were the first hospitalizations in this period. Patients who were less than 18 years old, hospital stay less than 48 h, pregnant or lactating women, the diagnosis of bronchiectasia, bronchogenic carcinoma, and other chronic respiratory disease, and cases with incomplete clinical data (> 10%) were excluded from the study.

The study was evaluated and approved by the Ethics Committee of Shanghai Fifth people’s Hospital (2021 Ethics Approval No. 242). All personal information was de-identified before further analysis.

Data collection

Databases were built up to collect clinical information: (1) Demographic data, i.e., age, sex, body-mass index, smoking status, inpatient stay, hospitalization expenditure. (2) Initial clinical symptoms, i.e., comorbidities, on admission vital signs, clinical complications. (3) Laboratory examination and imaging examination, i.e., routine analysis of blood, blood biochemistry, inflammatory index, blood coagulation function, examination of sputum etiology, arterial blood gas analysis, lung function, pulmonary CT imaging, B-ultrasound examination. (4) Treatment, i.e., antibiotic use, glucocorticoid use, mechanical ventilation condition, treatment outcome. (5) The follow-up, inhaling preparations at a stable stage, readmission at 30 days, 90 days and 180 days after discharge, death at 180 days.

Statistical analysis

All statistical analyses were performed using IBM SPSS 25.0 and GraphPad Prism 9.4.1. Patients were divided into two groups (male group and female group) according to sex. Continuous variables conforming to the normal distribution were presented as means ± SD, those that did not conform were expressed as the median (interquartile range), Categorical data are presented as frequencies and percentages. The data that met the assumptions of normality and homogeneity of variance were compared using two-tailed Student t-tests (t), the Welch correction was applied if the data did not conform to the normality assumption by the homogeneity of variance test, while those that did not meet the normality assumption were subjected to Mann–Whitney U test. Categorical variables were analyzed by Pearson Chi-square or Fisher exact tests. Study outcomes the composite end point was readmission or death, Kaplan–Meier curves and Cox proportional hazards analyses also were performed to examine the composite endpoint. In addition, we used logistic regression to compare which risk factors play a critical role as determinants of readmission to the hospital within 180 days between the two group. A value of p < 0.05 was considered statistically significant.

Results

Demographic characteristics

We reviewed medical case records from 1 January 2019 to 31 December 2021. Finally, 352 patients with AECOPD met our inclusion criteria and were included. The patients were divided into a female group (72 cases) and male group (280 cases). The mean age of female group was significantly higher than male group (78.07 ± 8.27 vs 74.13 ± 9.02, P = 0.001), and the same with BMI (24.18 ± 4.74 vs 22.42 ± 4.26, P = 0.01), but few women were current- or ex-smokers (2.78% vs 71.79%, P < 0.001) (Table 1).

Table 1 Demographics and clinical characteristics of the overall population.
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Clinical characteristics

Some clinical symptoms varied significantly among members of the two groups, such as increased coughing (76.4% vs. 86.4%, P = 0.036) and paroxysmal nocturnal dyspnea (8.3% vs. 2.1%, P = 0.027), there was no difference in sputum, dyspnea and pyrexia. In clinical complications, the female group significantly higher proportion of bronchiectasis (13.9% vs. 3.9%, P = 0.004) and higher CCI [1.5 (1,2.75) vs. 1 (1,2), P = 0.005], but differences in other complications between the two groups were not significant (Table 1).

Laboratory examinations

Compared to the male group, the female group had lower eosinophils (0.05 ± 0.08 vs 0.09 ± 0.21, P = 0.02), monocytes (0.45 ± 0.29 vs 0.54 ± 0.31, P = 0.033), hemoglobin (121.10 ± 17.29 vs 131.90 ± 22.17, P < 0.001), total bilirubin [7.65 (5.45, 10.9) vs 8.9 (6.2, 12.38), P = 0.046], serum creatinine [72 (57.25, 96) vs 77 (68, 96), P = 0.029] and IgE [44.1 (18.9, 128.5) vs 75.4 (28.1, 210), P = 0.012]. The female group had significantly higher HbA1c% > 6% (58.33% vs 36.43%, P = 0.001), low density lipoprotein [2.69 (2.13, 3.39) vs 2.45 (1.99, 2.99), P = 0.034], BNP [454 (199.25, 1742.5) vs 244.5 (116.25, 822.25), P = 0.001], D-dimer [0.78 (0.47, 1.83) vs 0.54 (0.29, 1.01), P = 0.001]. Differences in WBCs, neutrophils, platelets, CRP, PCT, ESR, albumin, pH, PaO2 and PaCO2 were not significant (Supplemental Table 1).

Pulmonary function test, B-ultrasound and radiographic imaging

The female group had significantly higher FEV1/FVC (66.58 ± 11.73 vs. 56.26 ± 12.56, P < 0.001) over the male group and the GOLD group 4 were markedly lower (7.69% vs. 21.68%, P = 0.047).There was no statistically significant difference between the two groups in terms of pulmonary artery systolic pressure and pleural effusion. Emphysema (43.1% vs. 82.9%, P < 0.001), bullae (1.4% vs. 15.0%, P = 0.002) and interstitial lung abnormalities (22.2% vs. 35.4%, P = 0.034) was significantly less common among the female group, compared to the male group (Supplemental Table 1).

Treatment and outcome

Intravenous antibiotic and glucocorticoid use, mechanical ventilation and outcome in both groups had no statistical significance (Supplemental Table 2).

Follow-up after hospital discharge

Medications used after discharge were compared. The female group showed significantly lower in use LABA/LAMA/ICS (Long-acting β2 agonist, LABA; Long-acting anticholinergics, LAMA; Inhaled corticosteroids, ICS) (15.5% vs. 34.5%, P = 0.002), but higher use of LABA/ICS (40.8% vs. 27.7%, P = 0.035). Differences in use LAMA and LAMA/LABA were not significant (Table 2).

Table 2 Followed up data after discharge of the two groups.
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The patients were followed up for 30 days, 90 days, 180 days after the discharge from the hospital. In female group, the rates of time to readmission for 30 days, 90 days, and 180 days from the time of admission were 9.96%, 20.9%, and 23.88%, while the male group were 8.3%, 16.23%, 24.91%, respectively. However, all these differences were not statistically significant in hospital readmissions (Table 2).

Study outcomes the composite end point was readmission or death, survival analysis using the Kaplan–Meier survival curve did not show any difference between the two groups for the composite endpoint (HR = 0.76, 95% CI: 0.46–1.25, log-rank P = 0.317) (Fig. 1). Cox proportional hazards analyses also did not show any difference between the two groups (HR = 1.325, 95% CI: 0.762–2.303, P > 0.05) (Table 3).

Fig. 1
figure 1

Kaplan–Meier survival curve of the two groups.

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Table 3 COX regression analysis of two groups.
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Factors associated with readmission to the hospital within 180 days

Univariate and multivariate logistic regression analyses were compared in the study population. The multivariate analysis incorporated seven factors according to the results of the univariate regression analysis, The results showed that readmission was independently associated with increased course of disease (P = 0.032), combined with chronic pulmonary heart disease (P = 0.011), and combined with peptic ulcer (P = 0.044). Conversely, there was no correlation between sex and readmission (P = 0.304) (Fig. 2).

Fig. 2
figure 2

Factors associated with readmission to the hospital within 180 days.

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Discussion

COPD causes death for approximately 3 million people each year and is the third leading cause of death worldwide in 20191. It seriously affects the patients’ physical and mental health and brings heavy mental and economic burdens to the society, patients and families. Our study was aimed at describing the clinical characteristics of, and the outcomes of AECOPD patients between different sex to help provide a better understanding of the population and identify certain features that may drive individualized therapy. In this study, we found that women in the first AECOPD hospitalizations tended to be older, less smoker, higher mean BMI, more often had bronchiectasis, lower eosinophils and IgE, better FEV1/FVC ratios, less emphysema, bullae and interstitial lung abnormalities, and were less likely to use LABA/LAMA/ICS, but there was no clear difference between the two groups in the short-term prognoses. The multivariate logistic regression analysis showed that readmission was independently associated with increased course of disease, combined with chronic pulmonary heart disease, and combined with peptic ulcer but not with sex.

Cigarette smoking is a major cause of COPD. The results of this study show that smoking was performed more commonly on male patients (71.79%) compared to the female patients (2.78%), and similar study findings from abroad also supported this finding8,9. This may explain why COPD prevalence was significantly higher among men than women. Besides this, some research shows that COPD is characterized by different phenotypes and clinical presentations. Study shows that biomass fuel is highly prevalent in China, and women are still the main bearers of housework so that they have relatively more access to biomass fuel10. It has been reported that smokers are more likely to develop emphysema than those exposed to biomass fuel. Camp et al. found that female COPD patients exposed to biomass smoke had less emphysema but more air retention than those exposed to e-tobacco smoke, suggesting that biofuel-induced COPD may be a respiratory tract-dominated phenotype11. In this study, we found that men had more emphysema, bullae, and interstitial lung abnormalities, but lower FEV1/FVC ratios than women, demonstrating these same findings in our study. Therefore, this study shows that different approaches to preventive measures should be taken according to sex.

A crucial pathologic feature of COPD is airway inflammation and remodeling. Eosinophils are pro-inflammatory effector cells which release pleiotropic chemokines, cytokines and cytotoxic granules such as eosinophil peroxidase and eosinophil-derived neurotoxin, play a role in the immune response to inflammation and infection. Couillard et al. found the eosinophil count elevated was associated with an increased risk of readmission12. The main finding of this study was that the eosinophil count and EOS% ≥ 2% increase in the male patients compared with the female patients, which is consistent with the relevant results from both domestic and foreign studies13,14. This may explain why male patients had a higher hospitalization rate than females. It has been suggested that airway eosinophilia facilitates responsiveness to bronchodilator and steroidal therapies15. Regarding clinical diagnosis and treatment, our study discovered that male patients were more likely to use LABA/LAMA/ICS, it also proves the rationality of clinical treatment. IgE is the major mediator in allergic responses and plays a pivotal role in airway inflammation and remodeling16. Many studies suggest that patients with COPD also have higher total IgE levels, and there are sex differences. Study found that elevated serum IgE is associated with the occurrence of exacerbations in men with COPD and with the risk of lung function decline, and they speculate that IgE-mediated pathways might be involved in the pathogenesis of exacerbations in men with COPD and in the pathogenesis of progressive airflow limitation in patients with elevated IgE levels17. This was also found in the studies of Marek et al.18, and they also found that there were higher total IgE levels in currently smoking than in not currently smoking men. In this study, the IgE levels of males were significantly higher than in females. Therefore, using antibodies targeting the IgE pathway for COPD may help in the prevention and control of disease, especially among men. But mechanism of sex-related and smoke-related differences in IgE level, further research is still needed.

Complications will also have an impact on the quality of life of COPD patients. Juan et al. found that cardiovascular comorbidities such as hypertension and ischemic heart disease are the most common comorbid combinations in the male patients, and the female patients were the most likely to have metabolic diseases such as osteoporosis19. Maeva et al. found that the proportion of subjects with ischemic heart disease and OSA was higher in males, but women tend to experience a greater prevalence of rhinitis and anxiety disorders5. In this study, the prevalence of bronchiectasis in female patients with COPD is higher compared to male patients which was inconsistent with the findings of other studies, but we found some abnormalities in metabolism-related indicators between different sex, such as glycosylated hemoglobin and low-density lipoprotein, which can also serve as fields for continued in-depth research in the future.

On average, each COPD patient suffers from 0.5 to 3.5 episodes of acute excerbations per year, and AECOPD is a major cause of death and causes huge medical expenditures2. Marshall et al. followed up for 3 years, the mortality was 10.8% in females and 11.2% in males, but the difference was not statistically significant5. In a 5-year follow-up study, Tamara et al. found women have higher 5-year survival rates than men (86.9% vs 76.3%, P < 0.001)6. However, we found that the mortality rate was lower but had a higher rate of readmission within 180 days, although the difference in our study did not reach statistical significance. In female group, the rates of time to readmission for 30 days, 90 days, and 180 days from the time of admission were 9.96%, 20.9%, and 23.88%, while the male group were 8.3%, 16.23%, 24.91%, respectively. Therefore, we further investigated the risk factors associated with short-term readmission. Our study found that readmission was independently associated with increased course of disease, combined with chronic pulmonary heart disease, and combined with peptic ulcer but not with sex. As a result, it is necessary to take the necessary measures to reduce readmissions.

Despite these strengths, our study has some limitations. First, Our study cohort showed considerable imbalance between groups (male group: n = 280; female group: n = 72). This imbalance could potentially affect our findings through several mechanisms, including increased risk of false discovery and reduced statistical power in the smaller group. The imbalanced groups may have affected our results in several ways, such as reduced ability to detect significant differences in the smaller group and potential overestimation of effects in the larger group. We acknowledge that despite statistical adjustments, some residual bias may remain and generalizability may be affected. Second, as a retrospective study, due to incomplete or inconsistent medical records and missing information, some information, such as risk factor exposure and objective questionnaires, was incomplete during clinical data collection. Selection bias may occur due to non-random participant selection and loss to follow-up, potentially affecting the study’s internal validity. The study was conducted from 2019 to 2021, and economic development, along with disparities between families, may influence the choice of inhaled drugs. Third, generalizability might be limited due to single-center or region-specific data collection. In future studies, we aim to design prospective studies with balanced group allocation, include larger sample sizes to improve statistical power, and consider multicenter approaches to achieve better balance.

Conclusion

Women in the first AECOPD hospitalizations tended to be older and less likely to use LABA/LAMA/ICS, possibly related to less smoking, better nutrition status, low levels of eosinophils and IgE level, and better lung function. The short-term readmission was independently associated with increased course of disease, combined with chronic pulmonary heart disease, and combined with peptic ulcer, but not with sex.