Change in Exacerbation Rate of Asthma Patients before and after COVID-19 Infection
Article information
Abstract
Background
Coronavirus disease 2019 (COVID-19) significantly impacted healthcare utilization and disease outcomes worldwide. During the pandemic, overall asthma exacerbations reportedly declined; however, the specific effect of COVID-19 infection on subsequent exacerbation patterns in asthma patients remains unclear.
Methods
Using a nationwide health insurance claims database from South Korea, we identified patients who had both asthma and a confirmed COVID-19 diagnosis in 2020. We defined the pre-COVID-19 period as the 12 months immediately preceding the date of each patient’s COVID-19 diagnosis, and the post-COVID-19 period as the 12 months following that date. Baseline characteristics, annual exacerbation rates, and direct medical costs were compared between these two timeframes.
Results
Among 82,825 confirmed COVID-19 cases, 2,965 patients with asthma met the inclusion criteria. Compared to the pre-COVID-19 period, the proportion of patients experiencing moderate and moderate-to-severe exacerbations decreased, whereas after COVID-19 infection, severe exacerbations increased. A binomial mixed model showed that moderate and moderate-to-severe exacerbations declined significantly (incidence rate ratio [IRR]=0.848, p<0.001; and IRR=0.912, p<0.001, respectively), while after COVID-19 infection, severe exacerbations increased (IRR=1.220, p<0.001). Of those who were non-exacerbators prior to COVID-19, 10.8% became exacerbators. This group was older, more frequently male, and had a greater comorbidity burden. Total direct medical costs escalated markedly from USD (2,965.50 to 4,850.41; p<0.001), particularly among those who developed as exacerbators after COVID-19 infection.
Conclusion
COVID-19 infection had a paradoxical impact on asthma exacerbations, reducing moderate exacerbations, while increasing severe events. The substantial rise in medical costs contributes to the economic burden of asthma care.
Introduction
Asthma is a prevalent chronic inflammatory disease of the airways that globally impacts almost 300 million people, and is characterized by variable airflow obstruction and hyperresponsiveness [1]. Preventing exacerbations remains a central goal of asthma management, as exacerbations reduce the patient’s quality of life, but also result in substantial healthcare utilization and increased economic burden [2,3]. Numerous triggers influence the risk and severity of these exacerbations, including respiratory viral infections, environmental allergens, air pollution, and treatment adherence [2,4].
The onset of the coronavirus disease 2019 (COVID-19) pandemic resulted in significant changes in global healthcare systems and daily life. It has infected more than 700 million people worldwide, and by May 19, 2024, was responsible for more than 7 million deaths [5]. Measures to avoid severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission that include mask-wearing, handwashing, and social distancing have been deployed, and have dramatically altered patterns of exposure to respiratory viruses and environmental irritants [6-8]. Previous studies have reported that these public health interventions were associated with a decrease in exacerbation rate in the era of COVID-19 [9-11]. However, the specific impact of SARS-CoV-2 infection on subsequent asthma outcomes remains unclear. Despite broad evidence of the decline in asthma exacerbation rates in the COVID-19 era, few investigations have studied the post-infection courses of patients with asthma.
The present study aimed to examine the impact of COVID-19 infection on future exacerbation rates. We hypothesized that prior SARS-CoV-2 infection alters airway inflammation and causes immune dysregulation, thereby increasing the risk of future exacerbations. Conversely, patients who experienced COVID-19 may develop heightened disease perception, leading to better treatment adherence and hygiene, which could decrease the risk of future exacerbations.
Materials and Methods
1. Study population and data collection
The Health Insurance Review and Assessment Service (HIRA) database consists of comprehensive health insurance claim data from all healthcare institutions in South Korea [12]. This nationwide database provides detailed and structured information on patient demographics, types of medical facility, clinical diagnoses (based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems [ICD-10] classification), prescribed medications, and direct medical costs. HIRA data are derived from the mandatory National Health Insurance (NHI) system, which ensures near-complete coverage of the Korean population.
For this research, data were extracted for patients diagnosed with COVID-19 and asthma between January 2020 and December 2020. COVID-19 diagnoses were based on the ICD-10 codes U071, U072, U09, and U099. Asthma patients were defined as individuals aged 15 years or older with a primary or secondary (up to the fifth position) diagnosis of asthma (ICD-10 code J45, J46) who throughout the study period were prescribed with inhaled corticosteroids (ICSs) containing inhalers at least twice in a year.
To evaluate clinical characteristics and medical costs before and after COVID-19 infection, data from January 2019 to December 2021 were analyzed. The pre-COVID-19 period was defined as the year preceding the data of each patient’s COVID-19 diagnosis, while the post-COVID-19 period was defined as the year following the diagnosis. Patients who experienced reinfection with COVID-19 within 1 year of their initial infection were excluded from the analysis.
2. Clinical parameters
The database provided information on general characteristics, such as age, sex, insurance type (NHI, Medical Aid, Veterans’ Insurance), and comorbidities that included allergic rhinitis, chronic rhinosinusitis, nasal polyp, atopic dermatitis, hypertension, diabetes, coronary heart disease, malignancy, and renal insufficiency. The modified Charlson comorbidity index (mCCI) was calculated based on previously described methodologies. Data on types of asthma medication usage were collected, including ICS, ICS plus long-acting beta agonist (LABA), and ICS plus LABA plus long-acting muscarinic antagonist (LAMA). Total direct medical costs were also gathered in the pre-COVID-19 and post-COVID-19 periods.
3. Exacerbation
The operational definition of a moderate exacerbation includes an outpatient visit, a diagnosis of asthma as indicated by ICD-10 codes J45−J46, and the prescription of antibiotics or systemic corticosteroids. A severe exacerbation is defined by an event satisfying all of the following: an emergency room visit or hospital admission; presence of ICD-10 code for asthma, pneumonia (J12−J17), pulmonary embolism (I26, I26.0, or I26.9), dyspnea (R06.0), or acute respiratory distress syndrome (J80); and the prescription of antibiotics or systemic corticosteroids. Events occurring within a 14 day period were regarded as a single exacerbation episode. All definitions of exacerbations were based on previously established criteria [13].
Exacerbators were defined as patients who experienced two or more moderate exacerbations or at least one severe exacerbation within a year. Non-exacerbators were identified as those with no exacerbations or only one moderate exacerbation, during the same period.
4. Statistical analysis
Categorical variables are presented as numbers (%), and continuous variables as the mean±standard deviation. McNemar’s test was employed to compare the proportion of patients who experienced exacerbations and medication usage between the pre-COVID-19 and post-COVID-19 periods. Differences in annual exacerbation rates for patients with asthma between the pre-COVID-19 and post-COVID-19 period were assessed using a binomial mixed model. One-year direct medical costs were analyzed between the pre- and post-COVID-19 periods in total, by post-COVID-19 exacerbation status, and by the type of medical use (inpatient and outpatient), using paired t-tests. Furthermore, among pre-COVID-19 non-exacerbators, baseline characteristics were compared between post-COVID-19 non-exacerbators and exacerbators. Continuous variables were analyzed with the Student’s t-test, and categorical variables with the chi-square test.
We also conducted two sensitivity analyses to support the robustness of our findings. First, to reduce the potential confounding effects of acute COVID-19 treatment, we excluded exacerbation events occurring within 14 days after the COVID-19 diagnosis date. Second, to account for the influence of comorbid chronic obstructive pulmonary disease (COPD), we repeated the analysis after excluding patients who met the predefined criteria for COPD: age ≥40 years, at least one diagnosis of COPD (ICD-10 J43−J44, excluding J430) up to the fifth secondary diagnosis, and prescription of COPD-related medications (i.e., ICS/LABA, LABA, LAMA, or ICS/LABA/LAMA) at least twice in the year prior to COVID-19 diagnosis.
All statistical analyses were performed using SAS Enterprise Guide version 7.1 (SAS Institute Inc., Cary, NC, USA). A p<0.05 was considered statistically significant.
5. Ethics
The study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital with registration number KC22ZISI0379, and performed in accordance with the principles of the Declaration of Helsinki. Informed consent from patients was waived by the Institutional Review Board of Seoul St. Mary’s Hospital.
Results
1. General characteristics of study subjects
Of 82,825 confirmed cases of COVID-19 infection in 2020, the number of eligible asthma patients without re-infection of COVID-19 within 1 year was 2,965 (Figure 1). Mean age of the population was 56.52±20.24 years; 48.1% were male (Table 1). Regarding insurance coverage, 86.7% held NHI, 11.3% had Medical Aid, and 2.0% were covered by Veterans’ Insurance. The most frequently observed comorbidity was allergic rhinitis (90.2%), followed by hypertension (48.7%), and diabetes mellitus (35.8%). Chronic rhinosinusitis and nasal polyps were reported in 26.5% and 2.6% of patients, respectively. The mean mCCI score was 3.68±2.50.
Flow chart of the study. COVID-19: coronavirus disease 2019.
General characteristics
2. Differences of annual exacerbation rate between the pre-COVID-19 and post-COVID-19 period
Compared with the pre-COVID-19 period, the proportion of patients experiencing moderate exacerbations and moderate-to-severe exacerbations decreased (44.1% to 37.4%, p<0.001; 46.8% to 42.7%, p<0.001, respectively), whereas severe exacerbation rose from 15.7% to 20.1% (p<0.001) (Table 2). In binomial mixed model, the incidence of moderate exacerbation and moderate-to-severe exacerbation significantly decreased during the post-COVID-19 period (incidence rate ratio [IRR]=0.848; 95% confidence interval [CI], 0.815 to 0.882; p<0.001; and IRR=0.912; 95% CI, 0.887 to 0.938; p=0.001, respectively) (Table 3). In contrast, the incidence of severe exacerbations was significantly higher in the post-COVID-19 period (IRR=1.220; 95% CI, 1.151 to 1.295; p<0.001). Sensitivity analyses showed consistent findings, except for severe exacerbations, which when events within 14 days of COVID-19 diagnosis were excluded, were no longer significant (Supplementary Tables S1-S4).
Differences in the number of patients who experienced exacerbations and in medication use between the pre-COVID-19 and post-COVID-19 periods
Differences of annual exacerbation rate between pre-COVID-19 and post-COVID-19 period (binomial mixed model)
3. Baseline characteristics between non-exacerbators and exacerbators in post-COVID-19 patients, among pre-CODVID-19 non-exacerbators
The number of non-exacerbators increased from 1,733 to 1,863, whereas the number of exacerbators changed from 1,232 to 1,102 before and after COVID-19 infection (Figure 2). Among patients who were non-exacerbators prior to COVID-19, 187 (10.8%) were reclassified as exacerbators (Table 4). Those who were reclassified into the exacerbator group were older, and showed a higher proportion of males. Allergic rhinitis and nasal polyps were also more prevalent among these patients. In addition, they exhibited higher rates of hypertension, diabetes mellitus, and renal insufficiency. The mean mCCI score was higher in the post-COVID-19 exacerbator group (3.61±2.33 vs. 3.26±2.29, p=0.047). In addition, baseline ICS plus LABA and triple therapy use were more frequent among those reclassified as exacerbators, than among those who remained non-exacerbators. Sensitivity analyses excluding events within 14 days of COVID-19 diagnosis showed consistent findings (Supplementary Table S5).
Sankey plot for exacerbation group before and after coronavirus disease 2019 (COVID-19) infection. FU: follow-up.
Differences in baseline characteristics between non-exacerbators and exacerbators in post-COVID-19 patients, among pre-COVID-19 non-exacerbators
4. Difference of medical usage before and after COVID-19 infection
The use of ICS for asthma declined from 13.6% to 9.4% (p<0.001), while no significant differences were observed in the usage rates of ICS plus LABA or triple therapy (Table 2). Table 5 shows that the total direct medical costs increased significantly from the pre- to post-COVID-19 period (United States dollar [USD] 2,965.50±6,499.06 to 4,850.41±12,154.56, p<0.001). This trend was comparable in both post-COVID-19 non-exacerbators and exacerbators. Inpatient costs also rose markedly from USD 5,563.99±8,887.92 to 7,459.51±15,860.07, affecting both non-exacerbators and exacerbators. Outpatient costs increased overall (USD 1,023.91±1,795.89 to 1,142.05±2,096.38, p<0.001), although this change did not reach statistical significance among non-exacerbators (p=0.155). In contrast, exacerbators experienced a significant rise in outpatient costs. Sensitivity analyses showed consistent findings (Supplementary Tables S6, S7).
Differences of direct medical costs between pre-COVID-19 and post-COVID-19 period
Discussion
In this nationwide study, we investigated the impact of COVID-19 infection on exacerbation rates and healthcare utilization in patients with asthma. We found contradictory results: while moderate and moderate-to-severe exacerbations declined after COVID-19 infection, severe exacerbations increased. Among individuals categorized as non-exacerbators prior to COVID-19, 10.8% transitioned to exacerbator status; these individuals tended to be older, more frequently male, and had a higher burden of comorbidities. In addition, although total direct medical costs increased substantially for both inpatient and outpatient services, the increase was particularly pronounced among those who became exacerbators.
A plausible explanation for the observed decrease in moderate and moderate-to-severe exacerbations is that patients who experienced COVID-19 subsequently became more vigilant about asthma self-management and personal hygiene [14]. Heightened awareness of respiratory symptoms and stricter adherence to controller medication, such as ICS, may have prevented asthma exacerbations [15]. As well, during the COVID-19 era, access to the healthcare system was limited due to the increased burden on medical facilities, and some patients may have avoided visiting hospitals for fear of viral exposure [16,17]. This reduced healthcare utilization could have led to underreporting of moderate exacerbations, particularly those that might have been managed at home without formal clinical documentation.
In contrast, the increase in severe exacerbations presents a paradox, for which there are several possible explanations. First, COVID-19 itself may have exerted a direct effect on the respiratory system in predisposed individuals, potentially altering their airway inflammation to cause more severe exacerbations [18]. Some patients with underlying asthma may have experienced dysregulated immune responses during or after SARS-CoV-2 infection, leading to prolonged or intensified airway inflammation. Second, changes in the accessibility of healthcare facilities during the pandemic might have contributed to delayed presentation [16,17]. Patients may have been reluctant to visit clinics or emergency departments for early or moderate symptoms due to fear of infection, leading to exacerbations escalating to severe levels by the time medical attention was sought. This avoidance could have increased the proportion of severe exacerbations captured in the claim data, as milder events were managed at home, and remained undocumented.
The economic burden caused by COVID-19 pandemic was tremendous, with USD 163.4 billion of direct medical cost being spent over the course of the era [19]. A previous study found that having asthma was not associated with increased medical cost associated with COVID-19 infection, except for those who used oral short-acting bronchodilators [20]. However, our study indicates that the economic burden of COVID-19 infection on individuals with asthma has increased. This increase in medical costs observed after the COVID-19 infection may be associated with the increase in severe exacerbations, which necessitate hospitalization, emergency care, and intensive therapies, thereby substantially escalating medical expenditures.
There are some limitations to this study. First, this is an observational study, which is limited in presenting causality between COVID-19 and exacerbation rates. Confounding factors, including healthcare accessibility, concurrent policy shifts, socioeconomic disparities, diagnostic accuracy and patients’ compliance, may have influenced the outcomes. Second, as this data was extracted based on the insurance reimbursement claims for a COVID-19 diagnosis, patients with mild symptoms, or those who were unable to access medical care, may have been under-reported. Those who had self-reported positive rapid antigen test results and tolerable symptoms may not have received medical treatment, and been under-reported in the insurance claims. Third, this data does not include important clinical features, including symptoms, asthma control status, and lung function test [21,22]. Fourth, there may be potential immortal-time bias, as patients who died during the observation period were not separately accounted for in the analysis. This may have led to underestimation of exacerbation rates in the post-COVID-19 period, as those with severe disease or a higher risk of mortality were not included in the follow-up analyses. Fifth, the decline in ICS use after COVID-19 infection may have influenced the observed exacerbation rates. Nearly half of the study population did not use ICSs, and ICS prescriptions significantly decreased post-infection. Given that ICS therapy plays a crucial role in asthma management, this change could have impacted exacerbation patterns. Sixth, in our study, the proportion of patients experiencing asthma exacerbations was higher than that reported in previous national assessments. This discrepancy may be explained by differences in asthma case definitions, data sources, and patient selection. Unlike the national asthma quality assessment, which includes only patients with asthma coded as the primary or first secondary diagnosis, our study considered diagnoses recorded up to the fourth position. In real- world clinical practice, physicians often down-code asthma diagnoses for patients who do not meet quality metrics (e.g., ICS use, regular follow-up), which may lead to underreporting in national datasets. Furthermore, our study focused on patients with confirmed COVID-19 infection, a subgroup likely to have more unstable asthma and higher risk for exacerbations. Seventh, in South Korea, the first phase of COVID-19 (January 20 to August 11, 2020) saw 35% of cases linked to the Shincheonji religious group, while the second phase (August 12 to November 12, 2020) was dominated by cases from mass gatherings [23]. These distinct transmission patterns differ from typical community spread, limiting generalizability. Finally, treatment-related factors such as ICS dose adjustments, inhaler device changes, and medication adherence, could not be evaluated, due to the limitations of claims data. The dataset provided by HIRA classified medications only by drug class, without detailed information on dosage or device type. As such, accurate assessment of adherence or device shifts was not feasible. Although no significant differences were observed in the use of ICS/LABA or triple therapy before and after COVID-19 infection, we acknowledge that unmeasured changes in treatment patterns may have influenced clinical outcomes.
In conclusion, this nationwide study provides novel insights into the impact of COVID-19 infection on asthma exacerbation rates and healthcare utilization. While moderate and moderate-to-severe exacerbations were decreased after COVID-19 infection in patients with asthma, severe exacerbations were significantly increased. This paradox may have been associated with post-infection immune dysregulation, behavioral change, and healthcare accessibility during the pandemic. Furthermore, the substantial increase in direct medical costs after COVID-19 infection indicates the financial burden associated with severe asthma outcomes post-COVID-19. These findings emphasize the need for tailored asthma management strategies in the post-COVID-19 era, including enhanced patient education, early intervention for severe exacerbations, and targeted healthcare policies to mitigate economic impacts. Future studies are warranted to address the limitations of observational data, and to explore long-term clinical outcomes.
Notes
Authors’ Contributions
Conceptualization: Choi JY, Rhee CK. Methodology: Choi JY, Rhee CK. Formal analysis: Kim KJ. Data curation: Kim KJ. Software: Kim KJ. Validation: Choi JY, Rhee CK. Investigation: Choi JY, Rhee CK. Writing - original draft preparation: Choi JY. Writing - review and editing: Choi JY, Rhee CK. Approval of final manuscript: all authors.
Conflicts of Interest
Joon Young Choi is an early career editorial board member and Chin Kook Rhee is a deputy editor of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Chin Kook Rhee received consulting/lecture fees from MSD, AstraZeneca, GSK, Novartis, Takeda, Mundipharma, Boehringer–Ingelheim, Teva, Sanofi, Organon, Roche, and Bayer.
Funding
This study was supported by grants from the Korean Environment Industry and Technology Institute through the Core Technology Development Project for Environmental Disease Prevention and Management, funded by the Korea Ministry of Environment (Grant number 2022003310008).
Supplementary Material
Supplementary material can be found in the journal homepage (http://www.e-trd.org).
Differences in the number of patients who experienced exacerbations and in medication use between the pre-COVID-19 and post-COVID-19 periods (sensitivity analysis excluding exacerbations within 14 days after COVID-19 diagnosis).
Differences of annual exacerbation rate between pre-COVID-19 and post-COVID-19 period (binomial mixed model) (sensitivity analysis excluding exacerbations within 14 days after COVID-19 diagnosis).
Differences in the number of patients who experienced exacerbations between the pre-COVID-19 and post-COVID-19 periods (sensitivity analysis excluding patients with COPD).
Differences of annual exacerbation rate between pre-COVID-19 and post-COVID-19 period (binomial mixed model) (sensitivity analysis excluding patients with COPD).
Differences in baseline characteristics between non-exacerbators and exacerbators in post-COVID-19 patients, among pre-COVID-19 non-exacerbators (sensitivity analysis excluding exacerbations within 14 days after COVID-19 diagnosis).
Differences of direct medical costs between pre-COVID-19 and post-COVID-19 period (sensitivity analysis excluding exacerbations within 14 days after COVID-19 diagnosis).
Differences of direct medical costs between pre-COVID-19 and post-COVID-19 period (sensitivity analysis excluding patients with COPD)