Abstract
Introduction
There is limited information on the uncontrolled status and burden of asthma among patients using inhaled corticosteroids (ICS) combined or not with long-acting β2-agonists (LABA) in China. This study aims to characterize the disease burden among these patients and identify risk factors for unfavorable outcomes.
Methods
This retrospective observational study utilized data from a regional Electronic Medical Record (EMR) database in China. Patients (≥ 12 years) with asthma having at least two prescriptions for medium-to-high dose ICS or ICS/LABA within any 6 months were identified from the Shanghai Medical Database between 2016 and 2020. Data on characteristics and treatment patterns 1-year pre-index (baseline) and disease burden 1-year post-index (follow-up) were obtained from the database. Uncontrolled asthma was defined based on exacerbations and specific treatment. A multivariate logistic regression model was used to identify risk factors associated with the follow-up adverse outcomes.
Results
A total of 35,900 patients with asthma receiving medium-to-high dose ICS or ICS/LABA were included. Of these, 10,842 (30.2%) were uncontrolled at baseline, exhibiting higher proportions of follow-up uncontrolled asthma (32.3% vs. 10.7%), corticosteroids use (16.8% vs. 3.9%), emergency room (ER) visits and hospitalizations due to exacerbations (22.3% vs. 5.2%), and total medical costs (9303.9 CNY vs. 8621.4 CNY) compared to patients who were controlled, all with p < 0.001. Type 2 (T2) biomarkers detection rates were less than 10% during follow-up. Uncontrolled asthma, older age, T2-related comorbidities, use of ≥ 2 controllers, a short-acting β2-agonist (SABA), and corticosteroids at baseline were significantly related to follow-up adverse outcomes.
Conclusion
A significant proportion of patients with asthma using medium-to-high dose ICS or ICS/LABA in China remain uncontrolled, resulting in greater disease and economic burden. Insufficient assessment of T2 inflammation and suboptimal treatment patterns represent the challenges in asthma management in China, potentially resulting in long-term adverse outcomes.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03714-0.
Keywords: Asthma, Uncontrolled, Risk factors, Disease burden, Electronic medical record
Key Summary Points
| Why carry out this study? |
| Limited studies have explored the characteristics, disease burden, and comprehensive risk factors contributing to uncontrolled status and severe exacerbations in Chinese patients with severe asthma. |
| This study investigated the clinical characteristics and disease burden of patients with asthma using medium-to-high dose inhaled corticosteroids (ICS) or ICS with long-acting β2-agonists (LABA) via Electronic Medical Record analysis, and identifies risk factors for uncontrolled disease progression. |
| What was learned from the study? |
| Patients with severe asthma exhibit significant burden, with elevated exacerbation rates, frequent corticosteroid reliance, and substantial economic costs. |
| The study elucidates risk factors for long-term adverse outcomes and unmet needs in severe asthma management, informing targeted intervention strategies. |
Introduction
Asthma is a serious global health problem [1]. It has been reported that the global prevalence of current asthma symptoms is 6–7% for adults [2]. In China, the CPH (China Pulmonary Health) study indicated the overall prevalence of asthma among Chinese adults (aged 20 years and above) was 4.2%, which represented approximately 45.7 million individuals with asthma [3].
As a significant subset of refractory asthma with multiple phenotypes, severe asthma accounts for 5–10% of all asthma cases [4, 5]. In China, severe asthma comprises 3.4–14.8% of patients with asthma [5–7]. Despite optimal asthma management, some patients experience frequent exacerbations or uncontrolled symptoms, leading to heightened disease burden. Patients with uncontrolled severe asthma exhibit increased healthcare resource utilization (HCRU), necessitating more frequent emergency room (ER) visits and hospitalizations, which incur elevated total and categorized medical costs. The liberal use of systemic corticosteroid therapy is also a growing concern due to its significant financial burden and side effects on patients with asthma [1, 5, 8–11].
Medium-to-high dose inhaled corticosteroid (ICS) or ICS plus long-acting beta-agonists (LABA) is a cornerstone therapy for asthma treatment [1, 12]. Persistent disease activity despite standardized medium-to-high dose ICS or ICS/LABA treatment signifies an elevated risk of exacerbation, greater disease burden, and a more complex clinical phenotype [13–17]. The patient population receiving medium- and high-dose ICS or ICS/LABA therapy is a potential group for severe asthma [18, 19]. Furthermore, accumulating data suggest that the presence of Type 2 (T2) inflammatory comorbidities and/or elevated biomarkers such as FeNO and blood eosinophils are prognostic factors often associated with an increased asthma disease burden [20, 21]. A thorough understanding of the clinical profiles and management strategies for these patients enables precise identification of high-risk individuals timely, and allows for tailored treatment optimization. However, study regarding the characteristics, disease burden, and the comprehensive risk factors that contribute to uncontrolled status and severe exacerbations of this specific patient cohort in China remains limited.
To address these gaps, this study aims to investigate the characteristics and disease burden among patients with asthma using medium-to-high dose ICS or ICS/LABA based on an electronic medical records (EMR) database, and to identify risk factors for uncontrolled status. These results would be crucial for developing effective personalized treatment strategies for patients with asthma.
Methods
Study Design
This study retrospectively analyzed data from the Shanghai EMR database, which contained anonymized health records of 30 million residents from 422 public medical institutions in Shanghai since 2015. Patients with asthma having at least two prescription records for ICS or ICS/LABA within any consecutive 12 months between January 1, 2016, and December 31, 2020, were retrieved from the database in June 2023. The day following the last medium-to-high dose of ICS or ICS/LABA prescription was defined as the index date. The year before and after the index date were defined as the baseline and follow-up periods, respectively (Fig. 1). The study relies solely on the EMR database, and no active interventions were performed during either the baseline or the follow-up periods.
Fig. 1.
Study design. Index date, the day following last prescription meeting the inclusion criteria; baseline period, 1 year before the index date; follow-up period, 1 year after the index date. HCRU healthcare resource utilization, OCS oral corticosteroids, SABA short-acting β-agonists, SCS systematic corticosteroid
Patients
Patients meeting the following criteria were included in the study: (1) diagnosed with asthma using ICD-10 codes (J45-46); (2) having at least two prescriptions for medium-to-high dose ICS or ICS/LABA (Table S1) within any 6 months; (3) age 12 years or older at index date. Patients with a diagnosis of cystic fibrosis, pulmonary fibrosis, lung cancer, or a history of autoimmune disease were excluded.
Individuals who met any of the following criteria during baseline were categorized as uncontrolled group, and the rest as the control group: (1) any asthma exacerbations, defined as hospital admission or ER visit with a primary diagnosis for asthma or asthma exacerbation or an outpatient visit with a diagnosis for asthma and one oral corticosteroid (OCS) prescription within 7 days (prescribed for < 30 days, and no subsequent OCS prescription); (2) treatment step-up, defined as an increase in the ICS dose from medium to high, or the prescription of at least one additional controller medication, including long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), oral theophylline, or OCS; or (3) ≥ 6 prescriptions of inhaled short-acting β2-agonist (SABA). The definition of uncontrolled asthma was derived from prior database-driven studies [22, 23]. The same criteria were used during the follow-up.
Data Collection and Assessment
Demographic and clinical information, including sex, age at index date, comorbidities, asthma-related medications, laboratory tests, examinations, visits, and costs were retrieved from the database. The analysis was based on the most recent laboratory and examination data available before the index date.
We evaluated the prevalence of T2 asthma among patients with any test result of T2 inflammatory biomarker, defined as meeting any of the following criteria: fractional exhaled nitric oxide (FeNO) ≥ 20 ppb, blood eosinophil count (BEC) ≥ 150/μL, or a positive allergen test, including specific immunoglobulin E (sIgE) and skin prick test (SPT) [1]. The prevalence of comorbidities was assessed based on physician-diagnosis (ICD-10). We counted the number of T2-related comorbidities in each patient, including atopic dermatitis (AD), allergic rhinitis (AR), chronic rhinosinusitis (CRS, with or without nasal polyps), and atopic conjunctivitis (AC). Asthma-related medications during baseline were assessed based on prescription records.
To evaluate the disease burden, we reassessed the control states patients receiving medium-to-high dose ICS or ICS/LABA during follow-up. The definition of uncontrolled status is consistent with the baseline. We calculated the incidence of exacerbation-related outpatient visits, ER visits and hospitalizations, use of corticosteroids, asthma-related examination rates, and both total and categorized costs during follow-up. The total healthcare costs were assessed based on actual billed amounts recorded in the database, including medication prescriptions, diagnostic tests, and ancillary services (e.g., hospitalization, nursing care) across outpatient, emergency, and inpatient visits. All expenditures were attributed to asthma-related encounters as defined by ICD-10 codes (e.g., J45/J46) linked to each visit type. All costs in the study were expressed in Chinese Yuan (CNY).
Statistical Methods
Descriptive statistics were used to summarize baseline characteristics and disease burden. For continuous variables, data were shown as mean ± standard deviation (SD); for categorical variables, data were shown as number and percentage of patients. We used the Wilcoxon test, χ2 test, or Poisson regression to assess differences between groups. Those with extreme outliers at or above the 99.9th percentile were excluded when assessing the visit frequencies and costs. We conducted two independent multivariable logistic regression models: Model 1 assessed uncontrolled status during follow-up; Model 2 evaluated a composite endpoint of exacerbation-related ER visits/hospitalization. Both were adjusted for age, sex, T2-related comorbidities, baseline treatment, and control status based on statistical significance and the results of previous research [24–30]. The odds ratio (OR) and the 95% confidence interval (CI) were estimated in multivariate logistic regression analyses. A two-tailed p value < 0.05 was considered to be statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
Ethical Approval
The study protocol and its amendments were approved by medical ethics committee of Beijing Chao-Yang Hospital (2023-KE-332). This study was conducted in accordance with the Ethical Guidelines for Biomedical Research Involving Human Subjects, the ethical principles of the Declaration of Helsinki, and all relevant regulations applicable to noninterventional studies. The need for informed consent was waived as data available in the database are standardized and anonymized.
Results
Study Populations
Between January 1, 2016, and December 31, 2020, a total of 712,623 individuals were diagnosed with asthma. After applying the inclusion and exclusion criteria, 35,900 patients receiving medium-to-high dose ICS or ICS/LABA were identified. Of these, 32,119 (89.5%) received medium-dose, and 3781 (10.5%) received high-dose ICS (at least one prescription for high-dose ICS or ICS + LABA). Of all included patients, 10,842 (30.2%) were uncontrolled at baseline, 7230 (20.1%) experienced at least one exacerbation, 4658 (13.0%) received step-up treatment, and 998 (2.8%) had six or more SABA prescriptions in a year prior the index date (Fig. 2).
Fig. 2.
Flowchart of patient selection and grouping. ICS inhaled corticosteroid, LABA long-acting β-agonist, SABA short-acting β-agonists
Baseline Clinical Characteristics
The baseline characteristics of patients receiving medium-to-high dose ICS or ICS/LABA are presented in Table 1. The age at the index date was 57.2 ± 16.2 (mean ± SD) years old. Female patients constituted 50.9% of the study population.
Table 1.
Baseline characteristics and treatment pattern of patients receiving medium-to-high dose ICS or ICS/LABA
| Total (N = 35,900) | Baseline uncontrolled (N = 10,842) |
Baseline controlled (N = 25,058) |
p | |
|---|---|---|---|---|
| Age, years, mean ± SD | 57.2 ± 16.2 | 56.7 ± 15.7 | 57.4 ± 16.5 | < 0.001 |
| Age group, n (%) | < 0.001 | |||
| < 30 | 1989 (5.5) | 625 (5.8) | 1364 (5.4) | |
| [30,40) | 4288 (11.9) | 1228 (11.3) | 3060 (12.2) | |
| [40,50) | 4654 (13.0) | 1374 (12.7) | 3280 (13.1) | |
| [50,60) | 6537 (18.2) | 2132 (19.7) | 4405 (17.6) | |
| [60,70) | 10,765 (30.0) | 3442 (31.7) | 7323 (29.2) | |
| ≥ 70 | 7667 (21.4) | 2041 (18.8) | 5626 (22.5) | |
| Female, n (%) | 18,274 (50.9) | 5482 (50.6) | 12,792 (51.0) | 0.397 |
| T2 asthma, n/N (%)a | 4555/6060 (75.2) | 2878/3814 (75.5) | 1677/2246 (74.7) | 0.490 |
| BEC ≥ 150/μL | 3453/5225 (66.1) | 2185/3394 (64.4) | 1268/1831 (69.3) | < 0.001 |
| FeNO ≥ 20 ppb | 114/154 (74.0) | 114/154 (74.0) | n.a.b | n.a.b |
| sIgE+/SPT+ | 1690/2116 (79.9) | 1098/1377 (79.7) | 592/739 (80.1) | 0.840 |
| Number of T2-related comorbidities, n (%) | < 0.001 | |||
| 0 | 22,339 (62.2) | 6320 (58.3) | 16,019 (63.9) | |
| 1 | 9951 (27.7) | 3209 (29.6) | 6742 (26.9) | |
| 2 | 3225 (9.0) | 1168 (10.8) | 2057 (8.2) | |
| ≥ 3 | 385 (1.1) | 145 (1.3) | 240 (1.0) | |
| Treatment pattern, n (%) | ||||
| ICS | 543 (1.5) | 136 (1.3) | 407 (1.6) | 0.008 |
| ICS/LABA | 35,357 (98.5) | 10,706 (98.7) | 24,651 (98.4) | 0.008 |
| ICS nebulization | 1657 (4.6) | 1400 (12.9) | 257 (1.0) | < 0.001 |
| OCS | 2758 (7.7) | 2721 (25.1) | 37 (0.1) | < 0.001 |
| Intravenous corticosteroids | 2367 (6.6) | 2002 (18.5) | 365 (1.5) | < 0.001 |
| LTRA | 13,391 (37.3) | 6394 (59.0) | 6997 (27.9) | < 0.001 |
| LAMA | 3680 (10.3) | 1872 (17.3) | 1808 (7.2) | < 0.001 |
| Oral theophylline | 1561 (4.3) | 904 (8.3) | 657 (2.6) | < 0.001 |
| Intravenous theophylline | 3826 (10.7) | 3328 (30.7) | 498 (2.0) | < 0.001 |
| SABA | 9811 (27.3) | 5013 (46.2) | 4798 (19.1) | < 0.001 |
| SAMA | 777 (2.2) | 482 (4.4) | 295 (1.2) | < 0.001 |
| Antibiotics | 5761 (16.0) | 3143 (29.0) | 2618 (10.4) | < 0.001 |
| Expectorants | 5129 (14.3) | 3182 (29.3) | 1947 (7.8) | < 0.001 |
| Antihistamines | 1006 (2.8) | 504 (4.6) | 502 (2.0) | < 0.001 |
| Biologics | 138 (0.4) | 93 (0.9) | 45 (0.2) | < 0.001 |
| Number of controllers, n (%) | < 0.001 | |||
| ≤ 1 | 19,482 (54.3) | 2879 (26.5) | 16,603 (66.3) | |
| 2 | 12,526 (34.9) | 4907 (45.3) | 7619 (30.4) | |
| ≥ 3 | 3892 (10.8) | 3056 (28.2) | 836 (3.3) | |
| OCS prescription times, n (%) | < 0.001 | |||
| 0 | 33,142 (92.3) | 8121 (74.9) | 25,021 (99.9) | |
| 1 | 1892 (5.3) | 1859 (17.1) | 33 (0.1) | |
| ≥ 2 | 866 (2.4) | 862 (8.0) | 4 (< 0.1) | |
| SABA prescription times, n (%) | < 0.001 | |||
| 0 | 26,089 (72.7) | 5829 (53.8) | 20,260 (80.9) | |
| 1 | 5233 (14.6) | 2215 (20.4) | 3018 (12.0) | |
| 2 | 1826 (5.1) | 870 (8.0) | 956 (3.8) | |
| ≥ 3 | 2752 (7.6) | 1928 (17.8) | 824 (3.3) | |
T2 asthma was defined as meeting any of the following criteria: FeNO ≥ 20 ppb, BEC ≥ 150/μL, or a positive allergen test, including sIgE and SPT. T2-related comorbidities included AD, AR, CRS and AC. Controllers included LABA, LTRA, LAMA, oral theophylline, and OCS. OCS included prednisone, prednisolone, and dexamethasone tablets
AC atopic conjunctivitis, AD atopic dermatitis, AR allergic rhinitis, BEC blood eosinophil count, CRS chronic sinusitis (with or without nasal polyps), FeNO the fractional exhaled nitric oxide, ICS inhaled corticosteroid, LABA long-acting β-agonist, LAMA long-acting muscarinic antagonists, LTRA leukotriene receptor antagonists, OCS oral corticosteroid, SABA short-acting β-agonists, SAMA short-acting muscarinic antagonists, SD standard deviation, sIgE specific immunoglobulin E, SPT skin prick test, T2 asthma type 2 asthma
aN number of patients with any relevant test result; n number of patients with at least one positive test result
bn.a. the proportion could not be calculated due to the absence of recorded FeNO test results in the control group
In the uncontrolled group, the prevalence of T2 asthma was above 75.5% among patients with relevant test results, with proportions of 64.4% for BEC ≥ 150/μL, 74.0% for FeNO ≥ 20 ppb, and 79.7% for positive allergen tests (sIgE+ or SPT+).
The study population exhibited a prevalence of 42.2% for eczema, marking it as the predominant comorbidity across both controlled and uncontrolled groups. Other common comorbidities (with a prevalence of 20% or higher) included allergic rhinitis (31.8%), diabetes (29.0%), osteoporosis (27.6%), chronic obstructive pulmonary disease (COPD, 25.7%), and cataract (20.6%). Notably, the uncontrolled group exhibited a significantly higher prevalence of T2-related comorbidities compared to the controlled group (Fig. 3).
Fig. 3.
Comorbidities prevalence of patients with asthma receiving medium-to-high dose ICS or ICS/LABA. *p < 0.05; **p < 0.001. AC atopic conjunctivitis, AD atopic dermatitis, AR allergic rhinitis, COPD chronic obstructive pulmonary disease, CRS chronic sinusitis, CRSwNP chronic sinusitis with nasal polyp, GERD gastroesophageal reflux diseases, ICS inhaled corticosteroid, LABA long-acting β-agonist
Baseline Treatment Pattern
The treatment patterns at baseline for patients are detailed in Table 1. Predominantly, 1.5% of the patients received ICS alone, and 98.5% received ICS/LABA. LTRA emerged as the second frequently prescribed controller in both groups, with a significantly higher utilization rate of 59.0% in the uncontrolled group, compared to 27.9% in the controlled group (p < 0.001). SABA was the most prevalent reliever among all patients, adopted by 46.2% of the uncontrolled patients and 19.1% of the controlled ones (p < 0.001).
In the uncontrolled group, 45.3% of patients used two types of controllers (ICS/LABA, OCS, LTRA, LAMA, or oral theophylline), and 28.2% used three or more, significantly higher than in the controlled group (30.4% and 3.3%, respectively, p < 0.001). Regarding prescription rates for OCS and SABA, 8.0% of uncontrolled patients received two or more OCS prescriptions, and 17.8% had three or more SABA prescriptions, compared to < 0.1% and 3.3% in the controlled group, respectively (p < 0.001).
Disease Burden During Follow-up
The results on disease burden of the patients receiving medium-to-high dose ICS or ICS/LABA during follow-up are summarized in Table 2. Among patients uncontrolled at baseline, 32.3% remained uncontrolled exhibiting an annualized exacerbation rate of 1.69 (95%CI: 1.65–1.72) per year. In the baseline-controlled group, a transition to uncontrolled status occurred in 10.7% (p < 0.001) of patients, with a significantly lower annualized exacerbation rate of 0.28 (95%CI: 0.27–0.29, p < 0.001) per year.
Table 2.
The disease burden of patients receiving medium-to-high dose ICS or ICS/LABA during follow-up
| Total (N = 35,900) |
Baseline uncontrolled (N = 10,842) |
Baseline controlled (N = 25,058) |
p | |
|---|---|---|---|---|
| Follow-up uncontrolled, n (%) | 6166 (17.2) | 3497 (32.3) | 2669 (10.7) | < 0.001 |
| Annualized exacerbation rates (/year), (95%CI) | 0.79 (0.77, 0.80) | 1.69 (1.65, 1.72) | 0.28 (0.27, 0.29) | < 0.001 |
| Corticosteroids besides ICS, n (%) | 2794 (7.8) | 1822 (16.8) | 972 (3.9) | < 0.001 |
| ICS nebulization | 998 (2.8) | 656 (6.1) | 342 (1.4) | < 0.001 |
| OCS | 1170 (3.3) | 834 (7.7) | 336 (1.3) | < 0.001 |
| Cumulative dose (mg), Mean ± SD | 609.0 ± 824.7 | 696.7 ± 886.5 | 388.1 ± 589.0 | < 0.001 |
| Intravenous corticosteroids | 1383 (3.9) | 932 (8.6) | 451 (1.8) | < 0.001 |
| Test and examination, n (%) | ||||
| PF | 2976 (8.3) | 1319 (12.2) | 1657 (6.6) | < 0.001 |
| CT | 688 (1.9) | 409 (3.8) | 279 (1.1) | < 0.001 |
| BEC | 3440 (9.6) | 1884 (17.4) | 1556 (6.2) | < 0.001 |
| FeNO | 2890 (8.1) | 1212 (11.2) | 1678 (6.7) | < 0.001 |
| sIgE/SPT | 1080 (3.0) | 625 (5.8) | 455 (1.8) | < 0.001 |
| ER visits or hospitalizations n (%) | 3712 (10.3) | 2414 (22.3) | 1298 (5.2) | < 0.001 |
| ER visits, n (%)a | 2330 (6.5) | 1598 (14.7) | 732 (2.9) | < 0.001 |
| Frequency, Mean ± SD | 3.1 ± 4.2 | 3.6 ± 4.7 | 2.0 ± 2.2 | < 0.001 |
| Cost (CNY), Mean ± SDb | 1259.7 ± 1759.9 | 1433.0 ± 1947.1 | 876.7 ± 1163.9 | < 0.001 |
| Hospitalizations, n (%)a | 1690 (4.7) | 1062 (9.8) | 628 (2.5) | < 0.001 |
| Frequency, Mean ± SD | 2.3 ± 2.2 | 2.6 ± 2.5 | 1.8 ± 1.7 | < 0.001 |
| Duration (day), Mean ± SD | 12.1 ± 16.3 | 13.5 ± 18.5 | 9.8 ± 11.2 | < 0.001 |
| Cost (CNY), Mean ± SDb | 23,444.5 ± 27,696.5 | 23,953.3 ± 26,805.6 | 22,507.1 ± 29,272.1 | < 0.001 |
| Outpatient visits, n (%)a | 911 (2.5) | 639 (5.9) | 272 (1.1) | < 0.001 |
| Frequency, Mean ± SD | 1.5 ± 1.0 | 1.6 ± 1.1 | 1.2 ± 0.5 | < 0.001 |
| Cost (CNY), Mean ± SDb | 561.7 ± 836.1 | 593.9 ± 934.4 | 486.7 ± 535.6 | < 0.001 |
| Total asthma cost (CNY), Mean ± SDc | 9069.1 ± 19,751.4 | 9303.9 ± 19,384.5 | 8621.4 ± 20,432.4 | < 0.001 |
| Medication | 3446.3 ± 7580.6 | 3878.4 ± 8097.5 | 2611.9 ± 6387.3 | < 0.001 |
| Test & Examination | 3988.1 ± 5434.3 | 4225.9 ± 5829.7 | 3542.1 ± 4572.0 | 0.177 |
BEC blood eosinophil count, CT computed tomography, ER emergency room, FeNO fractional exhaled nitric oxide, ICS inhaled corticosteroid, LABA long-acting β-agonist, OCS oral corticosteroids, PF pulmonary function, SD standard deviation, sIgE specific immunoglobulin E, SPT skin prick test
aIndicators were calculated within patients who had corresponding visits with main diagnosis of asthma exacerbation. Patients with extreme outliers at or above 99.9th percentile were excluded
bThe total cost per patient incurred by corresponding visits during follow-up
cThe total and categorized exacerbation-related cost per patient during follow-up
Of all patients, 7.8% used at least one corticosteroid besides ICS, with 2.8% of ICS nebulization, 3.3% of OCS, and 3.9% of intravenous corticosteroids. Typically, 7.7% of the baseline uncontrolled group utilized OCS, with a cumulative dose of 696.7 ± 886.5 mg, contrasting with 1.3% (p < 0.001) usage and a dose of 388.1 ± 589.0 mg (p < 0.001) in the baseline-controlled group. The detection rates of T2 biomarkers in all patients during follow-up were 9.6% for BEC, 8.1% for FeNO, and 3.0% for sIgE/SPT. All these rates were significantly higher in the baseline-uncontrolled group (p < 0.001). Patients who were uncontrolled at baseline had a significantly higher proportion requiring ER visits or hospitalizations due to exacerbations during follow-up compared to controlled patients (22.3% vs. 5.2%, p < 0.001). Similar findings were observed in the context of asthma-related tests, examinations, and medical visit frequency.
The total asthma-related cost during follow-up was 9069.1 ± 19,751.4 CNY, which was significantly higher in the baseline uncontrolled group (9303.9 CNY) compared to the controlled (8621.4 CNY, p < 0.001). The total medication cost was 3878.4 CNY in the baseline uncontrolled group and 2611.9 CNY in the controlled group (p < 0.001). The total examination costs for the two groups were 4225.9 CNY and 3542.1 CNY, respectively (p = 0.177). Additionally, significant differences were observed in the costs of outpatient visits, ER visits, and hospitalizations (all p < 0.001).
Risk Factors of Uncontrolled Asthma
Figure 4A presents the risk factors for follow-up uncontrolled status. The OR of age at index date increased gradually from 1.34 for [40, 50) years old to 1.66 for [60, 70) years old compared to the reference (< 30 years old, p < 0.05). For patients ≥ 70 years old, the OR value decreased (OR = 1.44), but was still statistically significant (p < 0.001). Uncontrolled status at baseline (OR = 2.34) and T2-related comorbidities were all found to significantly increase the risk of uncontrolled asthma, OR = 1.40, 1.80, 2.29 (all p < 0.001), with the increased number of T2-related comorbidities, respectively. Patients requiring two (OR = 1.12, p = 0.001) and three or more types of controllers (OR = 1.45, p < 0.001), the utilization of ICS nebulization (OR = 1.22, p = 0.001), intravenous corticosteroids (OR = 2.00, p < 0.001), OCS (OR = 1.94 for ≥ 2 prescriptions, p < 0.001), and SABA (OR = 1.24 for 1 prescription, 1.76 for 2, and 2.92 for ≥ 3 prescriptions, all p < 0.001) were identified as risk factors for follow-up uncontrolled status.
Fig. 4.
Multivariate logistic regression analysis of adverse outcomes during follow-up of patients with asthma receiving medium-to-high dose ICS or ICS/LABA: A dependent variable: follow-up uncontrolled status; B dependent variable: composite endpoint of asthma exacerbation-related ER visits or hospitalization. T2-related comorbidities included AD, AR, CRS, and AC. Controllers included LABA, LAMA, LTRA, oral theophylline, or OCS. AC atopic conjunctivitis, AD atopic dermatitis, AR allergic rhinitis,, CI confidence interval, CRS chronic sinusitis (with or without nasal polyps), ER emergency room, ICS inhaled corticosteroid, LABA long-acting β-agonist, LAMA long-acting muscarinic antagonist, LTRA leukotriene receptor antagonists, OCS oral corticosteroids, OR odds ratio, SABA short-acting β-agonists, SAMA short-acting muscarinic antagonists
The risk factors for ER visits and hospitalizations due to exacerbations during follow-up are shown in Fig. 4B. Notably, patients who used two types of controllers (OR = 0.88, p = 0.004) and had one OCS prescription (OR = 0.83, p = 0.015) at baseline had lower risk of experiencing ER visits and hospitalizations due to exacerbations. The findings of controlled and uncontrolled sub-groups analysis were generally consistent with those observed in all patients (Tables S2, S3).
Discussion
We have evaluated the characteristics, treatment, and disease burden in patients with asthma received medium-to-high dose ICS or ICS/LABA in real-world clinical practice using a medical database from Shanghai, China.
ICS is the cornerstone in asthma management. For patients who experience persistent symptoms and exacerbations, guidelines recommend use of ICS/LABA or a higher dose of ICS [1]. However, evidence indicates that treatment step-up does not consistently achieve complete asthma control. A Japanese study found that over 20% of patients with persistent asthma remained uncontrolled despite initiating medium-to-high doses of ICS/LABA [16]. Furthermore, higher ICS doses carry risks of systemic adverse effects and impose greater economic burden [31]. In our study, we defined the target population as patients receiving at least two medium-to-high dose ICS or ICS/LABA prescriptions within 6 months. These criteria, employed in retrospective database studies, effectively identify patients with severe asthma or those at high risk of asthma exacerbations [18, 19]. A total of 35,900 patients receiving medium-to-high dose ICS or ICS/LABA were included in the study, accounting for approximately 5.0% of total patients with asthma. This proportion aligns with a prior Japanese study reporting a similar rate of 3.9% [16]. Both are comparable to previously reported prevalence estimates for severe asthma [5–7]. Due to limited asthma control score records in our retrospective database, we assessed uncontrolled asthma using medical visits and medication prescriptions, a method well-suited for database-driven retrospective analyses [19, 32, 33]. The uncontrolled proportion was 30.2%, providing new insights based on clinical treatment patterns and adjusted definitions for assessing asthma control in China.
Regarding corticosteroids use during the follow-up period, higher utilization rates of OCS and intravenous corticosteroids were observed in patients with uncontrolled asthma, compared to those with controlled asthma. These findings align with a study based on a Japanese insurance claims database, which reported that patients with uncontrolled severe asthma had significantly higher usage rates of OCS (67.4% vs. 45.9%) and injectable corticosteroids (49.4% vs. 13.3%) than those with controlled disease (both p < 0.001) [32]. Systemic corticosteroids (SCS, oral or intravenous) are frequently prescribed for managing severe asthma in China. In a prospective study based on the Severe Asthma Web-based Database (SAWD), Wang et al. reported that 41.8% of patients with uncontrolled asthma in China had experienced at least one severe exacerbation in the previous year requiring OCS treatment [5]. However, frequent SCS use is associated with a heightened risk of significant adverse effects (AEs), including osteoporosis, hypertension, obesity, type 2 diabetes, gastrointestinal ulcers/bleeding, fractures, and cataracts [34]. Additionally, Wu et al. demonstrated that even low-dose SCS significantly increase the risk of new-onset AEs, HCRU, and associated costs [35]. Consequently, the World Allergy Organization and Respiratory Effectiveness Group recommend careful evaluation of the balance between SCS benefits and potential harms, advocating for alternative therapies when feasible [36].
Our study reports for the first time on the use of ICS nebulization, a modality commonly deployed as rescue therapy in Chinese emergency departments, while highlighting that patients remain susceptible to substantial long-term exacerbation risk despite acute symptom relief. This indicates that healthcare providers should be aware of the high prevalence of accumulated corticosteroid administration, not only SCS but also ICS nebulization for exacerbation resolution. It should be identified by clinicians through multidimensional evaluation or reminders provided by electronic systems in hospitals, due to their different application histories in the past.
During follow-up, the total asthma cost reached 9069.1 CNY, exceeding previous reports. Zhang et al. documented an average annual asthma-related cost of 2846.08 CNY for patients with severe asthma in Tianjin, China, using healthcare claims data from 2018–2020 [18]. This elevated cost may stem from study population selection, Shanghai's superior medical standards, robust economic conditions, and comprehensive insurance policies. Furthermore, we revealed that baseline-uncontrolled patients incurred significantly higher total healthcare costs than controlled patients during follow-up. This finding is consistent with earlier studies: Zhang et al. reported costs of 8506.83 CNY for patients with uncontrolled severe asthma versus 2105.70 CNY for controlled and 3559.35 CNY for sub-optimally controlled cases [18]. Similarly, Nagase et al. observed higher annual medical expenses for uncontrolled severe asthma in Japan (8346 USD) compared to controlled patients (5989 USD) [32].
Regarding the risk factors of uncontrolled asthma during follow-up, there is a certain positive correlation in patients between the incidence of adverse outcomes and age, a widely recognized risk factor for uncontrolled severe asthma [30, 37, 38]. Baptist et al. confirmed that asthma is prevalent among individuals over 65 years old, with this demographic experiencing higher incidence and mortality rates compared to other age groups [37]. Elderly patients with asthma are relatively common, yet often underdiagnosed and undertreated, exhibiting altered airway and systemic inflammation that responds poorly to corticosteroid therapy [38]. This may lead to higher corticosteroid use and more associated complications, resulting in greater disease burden. Consequently, strengthened asthma management for elderly individuals should be emphasized, focusing on both targeted detection and tailored medication.
Comorbidities are also reported as risk factors for uncontrolled asthma and are associated with poorer asthma-related outcomes. Previous studies have identified AR, nasal polyposis, CRS, and hypersensitivity as significant risk factors of uncontrolled asthma [39–41]. Based on our findings, the risk of adverse outcomes escalated with an increasing number of T2-related comorbidities, affecting both uncontrolled status and ER visits/hospitalizations due to exacerbations, which is similar to the effect of T2 biomarkers on severe asthma, including BEC, FeNO, and positive atopic status [28, 29]. While the deficiency in phenotypes identified among patients should be noted, we observed that the detection rates of T2 biomarkers in patients during follow-up were less than 10%, similar to previous reports of patients from China (8.2% for total IgE) [22]. In contrast, Japan demonstrated markedly elevated detection rates: 60.7% for BEC, 43.1% for total IgE, and 38.6% for FeNO in all patients with asthma [42]. The Global Initiative for Asthma has already recommended an assessment for the presence of potentially T2-related comorbidities [1]. The effectiveness of biologics in treating asthma with T2-related comorbidities has been well documented, and patients may gain systemic benefits [1, 43–45]. Future work is needed to strengthen the detection of biomarkers and to explore the association of biomarker profiles with comorbidities for patients with asthma.
Regarding the impact of treatment patterns on uncontrolled asthma, Tomisa et al. found that high SABA use (OR = 4.46, 4.03–4.93) and frequent OCS use (OR = 1.83, 1.64–2.05) were associated with uncontrolled asthma [25]. We find a similar impact of OCS even though its use is lower in China than in other areas. We observed that SCS therapy was the key treatment for asthma receiving medium-to-high dose ICS or ICS/LABA. However, the therapy failed to reduce adverse outcomes during follow-up. Clark et al. indicated that acute patients with asthma receiving intravenous corticosteroids were more likely to be admitted or experience a relapse event within 48 h (51% vs. 19%, p < 0.001) [26]. The regression model identified significant positive correlations between baseline corticosteroid and SABA use frequencies and adverse outcomes during follow-up. However, these correlations did not suggest that these medications directly cause poor control or worsened outcomes. Elevated treatment frequencies may indicate more severe underlying disease or persistent inflammation, which drives both treatment intensity and adverse events. The findings highlight unmet therapeutic needs—suggesting that current treatments, despite being used, fail to fully mitigate exacerbation risk—rather than implying that the drugs themselves contribute to poor outcomes.
Additionally, the use of SCS may lead to dependence and complications, indicating a clear need for better treatment options. At baseline, only 0.4% of patients received biologics, reflecting the early stage of biologic availability in China with only omalizumab, limited market access, and low physician awareness. Given the high incidence of T2 asthma and related comorbidities, more proactive administration of biologics should be considered for these individuals.
The limitations of the study are as follows. (1) Due to the limitations of the database, pharmacy retail data were not included in the database, potentially missing self-treatment cases, and those who failed to seek timely medical attention for specific reasons, thereby possibly underestimating the uncontrolled rate. Moreover, missing data on critical factors such as medication adherence and inhaler technique may also contribute to residual confounding in the model. Nonetheless, given that the medications concerned were prescription, the proportion of self-purchased medication was relatively low. Furthermore, for patients with asthma receiving medium-to-high dose ICS or ICS/LABA, self-treatment is frequently uncontrolled leading to hospitalization, thereby exerting minimal impact on the study's results. (2) The database used is specific to medical institutions in Shanghai, an urban area, and may not be representative of other regions, limiting the generalizability of the findings. (3) The study did not exclude the treatment costs associated with comorbidities, which may have resulted in an overestimation of the asthma-related costs. (4) Indirect costs and economic losses associated with asthma exacerbation were not considered. And (5), the study’s observational–retrospective design precludes causal inferences about risk factor—treatment–outcome associations, owing to unaddressed confounding. Future health economic evaluations utilizing alternative data sources and regionally diverse data are imperative to comprehensively assess the disease burden of asthma.
Conclusions
This large-scale analysis of regional electronic medical databases in China characterizes the disease burden among patients with asthma receiving medium-to-high dose ICS or ICS/LABA. Our findings indicate that elderly patients and those with a history of uncontrolled asthma face significantly heightened risks of exacerbations, increased HCRU, and elevated costs. Consequently, asthma management should prioritize targeted interventions for these high-risk subgroups. Furthermore, clinical assessments should be strengthened by incorporating standardized biomarker testing for T2 inflammation and routine screening for relevant comorbidities. Ultimately, optimizing management through rigorous risk stratification, personalized treatment plans, and digital adherence support is essential to improve patient outcomes and mitigate the long-term burden.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Medica Writing, Editorial, and Other Assistance
Medical writing was provided by Xinyan Wang, medical manager, of Hangzhou PRIME Life Science Co., Ltd. and was funded by Sanofi and Regeneron.
Author Contributions
Honglei Shi, Ying Wang, Min Wang, Kewu Huang jointly completed the manuscript writing. Dan Shen processed the data. Honglei Shi, Kewu Huang conceived the research guidance. Kewu Huang has full access to all data in the study and is ultimately responsible for the decision to submit for publication. All authors commented on previous versions of the manuscript and approved the final manuscript.
Funding
Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc. The journal’s Rapid Service Fee was funded by Sanofi and Regeneron Pharmaceuticals Inc.
Data Availability
The data that support the findings of this study are available from Shanghai Electronic Medical Record Data Center but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Shanghai Electronic Medical Record Data Center.
Declarations
Conflict of interest
Kewu Huang, Honglei Shi, and Ying Wang: nothing to disclose. Min Wang, Dan Shen, Sanofi employees, may hold stock and/or stock options in the company. Min Wang is currently affiliated with AstraZeneca.
Ethical Approval
The study protocol and its amendments were approved by medical ethics committee of Beijing Chao-Yang Hospital (2023-KE-332). This study was conducted in accordance with the Ethical Guidelines for Biomedical Research Involving Human Subjects, the ethical principles of the Declaration of Helsinki, and all relevant regulations applicable to noninterventional studies. The need for informed consent was waived as data available in the database are standardized and anonymized.
Footnotes
Prior Presentation: Part of the results had been presented in Annual Congress of Chinese Thoracic Society (CTS), September 2024, Hangzhou, China; and European Academy of Allergy and Clinical Immunology (EAACI) Congress, June 2025, Glasgow, UK.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from Shanghai Electronic Medical Record Data Center but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Shanghai Electronic Medical Record Data Center.