
==== Front
J Korean Med Sci
J Korean Med Sci
JKMS
Journal of Korean Medical Science
1011-8934
1598-6357
The Korean Academy of Medical Sciences

39228186
10.3346/jkms.2024.39.e255
Original Article
Infectious Diseases
High-Dose Corticosteroid Use in Severe to Critically Ill Patients With COVID-19: A Nationwide Population-Based Matched Cohort Study
https://orcid.org/0000-0002-1168-3666
Lee Raeseok 12
https://orcid.org/0000-0001-5392-3405
Cho Sung-Yeon 12
https://orcid.org/0000-0003-4655-0641
Lee Dong-Gun 12
https://orcid.org/0000-0003-2800-636X
Nho Dukhee 12
1 Division of Infectious Diseases, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
2 Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Address for Correspondence: Dong-Gun Lee, MD, PhD. Division of Infectious Diseases, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. symonlee@catholic.ac.kr
02 9 2024
05 8 2024
39 34 e25515 4 2024
09 7 2024
© 2024 The Korean Academy of Medical Sciences.
2024
The Korean Academy of Medical Sciences
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background

Systemic corticosteroids have become the standard of care for severe to critically ill patients with coronavirus disease 2019 (COVID-19). However, the real-world efficacy and safety outcomes associated with a higher dose of corticosteroids remain uncertain.

Methods

We conducted a nationwide, population-based, matched cohort study of severe to critically ill adult patients with COVID-19 between January 2020 and June 2021 in Korea using the National Health Information Database. Patients using systemic corticosteroids were included and high-dose corticosteroid use was defined as a daily mean prescribed dose of more than 6 mg of dexamethasone. We then employed a proportional hazard regression model to identify prognostic factors for 28-day all-cause mortality and conducted a Fine and Gray regression model to assess risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA).

Results

During the study period, 102,304 patients with COVID-19 were screened, 5,754 met the eligibility criteria, and 2,138 were successfully matched. The mean prescribed daily dose was 4.2 mg and 13.4 mg in the standard- and high-dose groups, respectively, and the mean duration of use was not different between the groups. High-dose corticosteroid use independently increased all-cause mortality at 28 days (adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.25–1.76) and 90 days (aHR, 1.63; CI, 1.44–1.85) after admission. Subgroup analysis revealed a statistically significant elevation in the risk of mortality among patients using low-flow or high-flow nasal cannulas, with aHRs of 1.41 and 1.46, respectively. No significant impact of high-dose steroids was observed, even in patients who underwent mechanical ventilation at 28 days (aHR, 1.17; CI, 0.79–1.72). As a safety outcome, high-dose corticosteroid use showed an association with the development of CAPA (aHR, 2.97; 95% CI, 0.94–9.43).

Conclusion

Among severe to critically ill patients with COVID-19, high-dose corticosteroid use was associated with increased 28-day all-cause mortality and showed a trend toward the development of CAPA.

Graphical Abstract

COVID-19
Glucocorticoids
Survival
COVID-19-Associated Pulmonary Aspergillosis
National Research Foundation of Korea http://dx.doi.org/10.13039/501100003725 NRF-2022R1I1A1A01070887
==== Body
pmcINTRODUCTION

Coronavirus disease 2019 (COVID-19) causes acute respiratory failure in approximately 12–17% of hospitalized patients.12 Systemic corticosteroids have become the cornerstone of treatment for severe and critically ill patients with COVID-19 since the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which reported beneficial survival outcomes without increasing the risk of secondary or super-infections.3

Although systemic corticosteroids improved survival in patients with COVID-19 who required oxygen support in well-designed clinical trials and meta-analyses, there are notable discrepancies in survival and complications between the studies.4 Although a dose of 6 mg/day of dexamethasone for up to 10 days has become the standard corticosteroid treatment protocol following the RECOVERY trial, the optimal dose, duration, and route of corticosteroids for treating severe COVID-19 remain controversial.356789 Furthermore, these dosage and duration parameters were established through clinical practices rather than evidence-based decision-making.10 In a recent clinical trial indicated that high-dose corticosteroid use in hypoxic patients not requiring ventilatory support significantly increased the risk of death.10 However, several studies have indicated that a higher dose of systemic corticosteroids over 10 days decreases mortality and recovery time.611

The increased risk of secondary infection, such as COVID-19-associated pulmonary aspergillosis (CAPA), due to systemic corticosteroid use for severe COVID-19 is concerning.121314 Previous retrospective observational studies have suggested that the dose and duration of systemic corticosteroid use is associated with developing CAPA.15161718 However, clinical trials and prospective studies have not found differences in secondary infections according to the use of systemic corticosteroids.357 These results had a limitation in that they did not predetermine the criteria for CAPA diagnosis as a safety outcome.19

This study aimed to investigate the clinical efficacy of high-dose corticosteroids compared to a standard dose in severe to critically ill patients with COVID-19 using nationwide, real-world, population-based data. We also attempted to identify the impact of a higher dose of systemic corticosteroids on developing CAPA.

METHODS

Data source and study population

This nationwide, population-based, matched cohort study used data from the National Health Insurance Service (NHIS) of Korea. The NHIS provides insurance coverage for various medical practices and established the National Health Information Database (NHID) in 2011, covering the entire population of Korea.20 The NHID comprises a set of data that includes eligibility, medical treatment, and healthcare provider databases.20

From this database, all hospitalized patients with diagnosis codes for COVID-19 and presenting with the disease for the first time between January 2020 and June 2021 were screened and patients with severe cases, defined by their oxygen requirements, were enrolled.21 A diagnosis of COVID-19 was identified using the International Classification of Diseases-10th revision (ICD-10) codes; U071, 072, and 109. The exclusion criteria were as follows: 1) outpatients with COVID-19; 2) < 18 years of age; 3) patients without eligibility record in the NHID; 4) patients with mild to moderate COVID-19 (without oxygen supplementation); 5) patients who were administered anti-mold active agents for over 2 weeks within 6 months before the diagnosis of COVID-19; 6) patients treated for COVID-19-associated mucormycosis (CAM) during hospitalization; and 7) patients who did not receive systemic corticosteroids. A detailed schematic flow of population selection is shown in Fig. 1.

Fig. 1 Schematic flow of patient selection from the National Health Information database.

CAM = COVID-19-associated mucormycosis, COVID-19 = coronavirus disease 2019, NHID = National Health Information Database.

Operational definitions

No previous studies have suggested a proven screening method for CAPA in medical databases. Through the consensus of four infectious diseases specialists, we defined CAPA as a prescription of anti-mold active agents for at least 1 week under the diagnosis codes for COVID-19. Unlike previous research that selected invasive pulmonary aspergillosis (IPA) through an operational definition, this study did not apply diagnostic codes of IPA for eligible patients, as through our research experience these codes were missed in nearly half of CAPA cases.1222 Rather than including diagnostic codes, we restricted antifungal agents use over 1 week to increase the robustness of the operational definition. Anti-mold active agents included triazoles (voriconazole, isavuconazole, posaconazole, and itraconazole) and polyenes (amphotericin B deoxycholate and liposomal amphotericin B). The validity of this operational definition was assessed in a previous multicenter, retrospective cohort study.1214 The degree of agreement by Cohen’s kappa was 0.713, with a 95% confidence interval (CI) of 0.494–0.931, which showed a substantial level of agreement.12 We defined CAM as patients who had the ICD-10 code for mucormycosis (B46) with the administration of anti-mold active agents over 1 week during hospitalization.

According to a previous clinical trial that defined the standard dose of corticosteroid, we included patients who received a daily mean prescribed dose of > 6 mg of dexamethasone or an equivalent in the high-dose corticosteroid group.3 Any dose lower than high-dose corticosteroids was considered as standard-dose group.

Definition of other cohort variables

Underlying comorbidities, such as venous thrombosis, diabetes mellitus, ischemic heart disease (IHD), congestive heart failure (CHF), chronic obstructive pulmonary disease, tuberculosis, chronic kidney disease, stroke, dementia, solid cancer, hematologic malignancies, human immunodeficiency virus, autoimmune rheumatic diseases, and history of transplantation were defined by ICD-10 codes with a prescription (Supplementary Table 1).23242526 Additional health measures from biannual health screening examinations, such as smoking (never, former, and current smoker), alcohol intake (hardly none/2–3 per month/1–2 per week as a social drinker/3–4 per week/almost every day as a heavy drinker), body mass index, and creatinine were included. Household income was derived from the insurance premium (first, second, third, and fourth quantiles) and the degree of disability was defined based on severity (none, mild to moderate, and severe). The level of respiratory support was defined based on the highest oxygen requirement during hospitalization.

Study outcomes

The primary efficacy endpoint of this study was all-cause mortality within 28 days of admission. The diagnosis of CAPA during hospitalization with the first diagnosis of COVID-19 was set as the safety outcome and the secondary endpoint of high-dose corticosteroid use. Another exploratory outcome was all-cause mortality assessed at day 90 of admission. The study population was followed up from hospitalization to the date of death or 90 days, whichever came first.

Statistical analysis

The age and the sex-matched cohort was retrieved from the high-dose corticosteroid group. The absolute standardized mean difference was used to examine the balance between covariate distribution. The baseline characteristics are presented as mean ± standard deviation for continuous variables and as frequencies with percentages for categorical variables. Normal distribution was checked using the Shapiro–Wilk test. Cox regression analysis presented with hazard ratio (HR) and CI was performed to identify the prognostic factors for all-cause mortality at 28 days after hospitalization. Predictors of CAPA development were calculated using Fine and Gray regression with the competing risk of death and development of CAPA. Significant variables in the univariate analysis and from other clinical studies were included to calculate adjusted HR.121327

Preplanned subgroup and sensitivity analyses were performed. Subgroup analyses according to age (< 60, 60–69, 70–79, and ≥ 80 years), sex, solid cancer, hematologic malignancies, and levels of respiratory support, which are well-known variables associated with mortality, were performed. The risk of mortality in the high-dose corticosteroid group compared to the standard-dose group was calculated for each subgroup. A sensitivity analysis was conducted excluding patients who died within 7 days of admission to identify whether the difference in the outcome was due to the early death of critically ill patients. To enhance the robustness of the study results, we conducted a sub-analysis in two cohorts: one administered with dexamethasone at a dosage of 5.5–6.0 mg/day from the standard-dose group, and another receiving doses > 12 mg/day from the high-dose group.

All statistical analyses were conducted using SAS software (version 9.4; SAS Institute, Cary, NC, USA), and matching was performed using R software version 4.1.0 (R Project for Statistical Computing, Vienna, Austria). All two-tailed tests, with P < 0.05 were considered statistically significant.

Ethics statement

The requirement of informed consent from individual patients was waived because the data were anonymized. The study protocol was reviewed and approved by the Institutional Review Board of Seoul St. Mary’s Hospital (No. KC21ZISI0404).

RESULTS

Demographics and clinical characteristics of the cohort study population

Between January 1, 2020, and June 30, 2021, 102,304 patients were screened, 5,754 met the eligibility criteria, and 2,138 of those who were administered standard-dose corticosteroids were successfully matched to a control group who were administered high-dose corticosteroids. In the matched cohort, the two groups had the same distribution of baseline demographics except for hospital type, region, and levels of respiratory support (Table 1).

Table 1 Baseline characteristics of the patients according to corticosteroid dose

Variables	Entire cohort	Matched cohort	
Standard-dose (n = 2,138)	High-dose (n = 3,616)	P value	Standard-dose (n = 2,138)	High-dose (n = 2,138)	P value	SMD	
Steroid, duration, days	11.7 ± 12.3	12.3 ± 10.0	0.033	11.7 ± 12.3	12.3 ± 9.8	0.102	0.04	
Steroid, mean daily dose,a mg	4.2 ± 1.2	13.4 ± 9.6	< 0.001	4.2 ± 1.2	13.5 ± 9.9	< 0.001	1.31	
Age, yr	70.6 ± 14.0	69.8 ± 13.3	0.040	70.6 ± 14.0	70.6 ± 13.7	0.892	< 0.01	
Sex (male)	1,096 (51.3)	2,060 (56.9)	< 0.001	1,096 (51.3)	1,096 (51.3)	1.000	< 0.01	
Household income (missing = 62)			0.331			0.510	0.03	
	First percentile	606 (28.6)	967 (27.0)	606 (28.6)	571 (27.0)	
	Second percentile	332 (15.7)	589 (16.5)	332 (15.7)	345 (16.3)	
	Third percentile	423 (20.0)	683 (19.1)	423 (20.0)	412 (19.4)	
	Fourth percentile	754 (35.7)	1,338 (37.4)	754 (35.7)	791 (37.3)	
Degrees of disability			0.647			0.720	0.02	
	None	1,674 (78.3)	2,863 (79.2)	1,674 (78.3)	1,688 (78.9)	
	Mild to moderate	268 (12.5)	424 (11.7)	268 (12.5)	269 (12.6)	
	Severe	196 (9.2)	329 (9.1)	196 (9.2)	181 (8.5)	
Smoking status (missing = 3,083)			0.104			0.631	0.02	
	Never/former	660 (69.1)	1,133 (66.0)	660 (69.1)	681 (68.1)	
	Current	295 (30.9)	583 (34.0)	295 (30.9)	319 (31.9)	
BMI (missing = 3,177)	25.4 ± 3.7	25.7 ± 3.7	0.022	25.4 ± 3.7	25.7 ± 3.5	0.075	0.08	
Creatinine (missing = 3,177)	0.9 ± 0.5	1.0 ± 1.8	0.160	0.9 ± 0.5	1.1 ± 2.2	0.098	0.07	
Alcohol intake (missing = 3,083)			0.501			0.307	0.04	
	Social drinker	856 (89.6)	1,552 (90.4)	856 (89.6)	910 (91.0)	
	Heavy drinker	99 (10.4)	164 (9.6)	99 (10.4)	90 (9.0)	
Hospital type			< 0.001			< 0.001	0.32	
	Referred	268 (12.5)	865 (23.9)	268 (12.5)	509 (23.8)	
	General	1,870 (87.5)	2,751 (76.1)	1,870 (87.5)	1,629 (76.1)	
Region of hospitals			< 0.001			< 0.001	0.20	
	Metropolitan area	1,269 (59.4)	2,503 (69.2)	1,269 (59.4)	1,474 (68.9)	
	Other	869 (40.6)	1,113 (30.8)	869 (40.6)	664 (31.1)	
Venous thrombosis	140 (6.6)	220 (6.1)	0.482	140 (6.6)	107 (5.0)	0.031	0.06	
Diabetes mellitus	1,430 (66.8)	2,361 (65.3)	0.218	1,430 (66.8)	1,406 (65.8)	0.437	0.02	
IHD/CHF	670 (31.3)	996 (27.5)	0.002	670 (31.3)	611 (28.6)	0.050	0.06	
COPD	465 (21.7)	731 (20.2)	0.166	465 (21.7)	436 (20.4)	0.277	0.03	
Tuberculosis	22 (1.0)	39 (1.1)	0.859	22 (1.0)	23 (1.1)	0.881	< 0.01	
CKD	183 (8.6)	320 (8.6)	0.706	183 (8.6)	187 (8.7)	0.828	< 0.01	
Stroke	760 (35.6)	1,188 (32.8)	0.038	760 (35.6)	740 (34.6)	0.522	0.01	
Dementia	25 (1.2)	42 (1.2)	0.978	25 (1.2)	30 (1.4)	0.497	0.02	
Solid cancer	219 (10.2)	472 (13.1)	0.002	219 (10.2)	261 (12.2)	0.042	0.06	
HMs	23 (1.1)	46 (1.3)	0.508	23 (1.1)	30 (1.4)	0.333	0.02	
HIV	4 (0.2)	2 (0.1)	0.203b	4 (0.2)	2 (0.1)	0.687b	0.02	
ARD	658 (30.8)	1,013 (28.0)	0.025	658 (30.8)	615 (28.8)	0.150	0.04	
HSCT	0 (0.0)	0 (0.0)	N/A	0 (0.0)	0 (0.0)	N/A	N/A	
SOT	1 (0.1)	3 (0.1)	1.000b	1 (0.1)	1 (0.1)	1.000b	< 0.01	
ICU admission	356 (16.7)	1,091 (30.2)	< 0.001	356 (16.7)	653 (30.5)	< 0.001	0.33	
Respiratory support			< 0.001			< 0.001	0.68	
	Nasal cannula	1,769 (82.7)	1,880 (52.0)	1,769 (82.7)	1,099 (51.4)	
	HFNC	267 (12.5)	1,109 (30.7)	267 (12.5)	659 (30.8)	
	Mechanical ventilation	102 (4.8)	627 (17.3)	102 (4.8)	380 (17.8)	
Overall mortality at 28-day	246 (11.5)	646 (17.9)	< 0.001	246 (11.5)	395 (18.5)	< 0.001	0.19	
Development of CAPA	3 (0.1)	30 (0.8)	0.001	3 (0.1)	17 (0.8)	0.002	0.09	
Data are presented as number. (%) or mean ± standard deviation unless otherwise indicated.

SMD = standardized mean difference, BMI = body mass index, IHD = ischemic heart disease, CHF = congestive heart failure, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, HMs = hematologic malignancies, HIV = human immunodeficiency virus, ARD = autoimmune rheumatic disease, HSCT = hematopoietic stem cell transplantation, N/A = not applicable, SOT = solid organ transplantation, ICU = intensive care unit, HFNC = high-flow nasal cannula, CAPA = COVID-19-associated pulmonary aspergillosis.

aDoses are calculated based on dexamethasone.

bFisher’s exact test for categorical variables was used.

The maximum follow-up period was 90 days after admission and the mean follow-up period was shorter in patients in the high-dose corticosteroid group (mean difference, 1.60 days; 95% CI, 0.67–2.54). Corticosteroid use commenced concurrently with or after respiratory support in 93.8% of patients in the standard-dose group and in 86.0% of patients in the high-dose group. The detailed baseline characteristics of the patients in the entire cohort and the matched cohort are presented in Table 1.

All-cause mortality at 28-days by corticosteroid dose and other prognostic factors

The incidence rate (IR) of 28-day mortality was 0.77 (95% CI, 0.68–0.87) per 100 patient days for the standard-dose group and 1.47 (95% CI, 1.33–1.62) for the high-dose matched control group. The Kaplan-Meier curve of overall mortality in the high-dose corticosteroid group at 28 days after hospitalization was significantly higher than that in the standard-dose corticosteroid group (246 of 2,138 [11.5%] vs. 395 of 2,138 [18.5%]; HR, 1.99; 95% CI, 1.70–2.34) (Fig. 2). High-dose corticosteroid use was the independent risk factor of mortality in the multivariate Cox regression analysis in the matched cohort (adjusted HR, 1.48; 95% CI, 1.25–1.76) (Table 2). Along with high-dose corticosteroids, old age, high levels of respiratory support, and comorbidities such as IHD, CHF, and stroke were shown to be associated with increased mortality in the multivariate analysis. The development of CAPA itself did not affect the mortality outcome. Detailed results are presented in Table 2.

Fig. 2 All-cause mortality at 28 days from the matched cohort, analyzed using the Kaplan-Meier method.

CI = confidence interval, HR = hazard ratio.

Table 2 All-cause mortality at 28 days assessed via Cox proportional hazard regression analysis

Variables	Cox univariate	Cox multivariate	
Crude HR	95% CI	P value	Adjusted HR	95% CI	P value	
Corticosteroid							
	Standard-dose	Reference			Reference			
	High-dose	1.99	1.70–2.34	< 0.001	1.48	1.25–1.76	< 0.001	
Age group, yr							
	< 60	Reference			Reference			
	60 ≤ age < 70	1.94	1.21–3.11	0.006	1.69	1.05–2.72	0.031	
	70 ≤ age < 80	3.38	2.18–5.24	< 0.001	2.52	1.60–3.95	< 0.001	
	≥ 80	7.21	4.74–10.99	< 0.001	5.12	3.31–7.94	< 0.001	
Sex (female vs. male)	1.18	1.01–1.37	0.041				
Household income							
	First percentile	Reference						
	Second percentile	0.95	0.74–1.22	0.672				
	Third percentile	1.04	0.83–1.31	0.726				
	Fourth percentile	1.07	0.88–1.30	0.497				
Degree of disability							
	None	Reference			Reference			
	Mild to moderate	1.31	1.07–1.61	0.010	1.01	0.82–1.25	0.895	
	Severe	0.93	0.71–1.21	0.589	0.92	0.70–1.21	0.549	
Smoking status							
	Never/former	Reference						
	Current	0.73	0.53–1.01	0.060				
BMI	0.96	0.92–1.01	0.089				
Creatinine	1.01	0.95–1.07	0.754				
Alcohol intake							
	Social drinker	Reference						
	Heavy drinker	0.43	0.21–0.87	0.019				
Hospital type							
	Referred	Reference			Reference			
	General	0.85	0.70–1.04	0.109	1.06	0.85–1.33	0.586	
Region of hospitals							
	Metropolitan area	Reference			Reference			
	Other	1.17	0.99–1.37	0.051	1.24	1.06–1.47	0.009	
Venous thrombosis	0.97	0.71–1.33	0.867	0.80	0.58–1.11	0.176	
Diabetes mellitus	1.40	1.17–1.68	< 0.001	1.02	0.84–1.23	0.874	
IHD/CHF	1.53	1.31–179	< 0.001	1.20	1.01–1.42	0.039	
COPD	1.48	1.25–1.76	< 0.001	1.13	0.94–1.34	0.191	
Tuberculosis	1.29	0.67–2.50	0.445				
CKD	1.21	0.95–1.55	0.118	0.94	0.73–1.22	0.656	
Stroke	1.84	1.58–2.15	< 0.001	1.27	1.08–1.51	0.004	
Dementia	1.42	0.84–2.42	0.192	0.85	0.50–1.46	0.555	
Solid cancer	1.49	1.21–1.85	< 0.001	1.35	1.09–1.67	0.007	
HMs	2.01	1.21–3.36	0.007	2.16	1.27–3.68	0.004	
HIV	0.63	0.09–4.47	0.644				
ARD	1.15	0.98–1.36	0.086				
HSCT	N/A						
SOT	N/A						
ICU admission	1.77	1.50–2.08	< 0.001	0.98	0.80–0.20	0.841	
Respiratory support							
	Nasal cannula	Reference			Reference			
	HFNC	3.09	2.59–3.69	< 0.001	2.62	2.15–3.18	< 0.001	
	Mechanical ventilation	3.39	2.77–4.16	< 0.001	3.40	2.62–4.42	< 0.001	
Development of CAPA	0.92	0.35–2.47	0.874	0.68	0.25–1.84	0.452	
HR = hazard ratio, CI = confidence interval, BMI = body mass index, IHD = ischemic heart disease, CHF = congestive heart failure, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, HMs = hematologic malignancies, HIV = human immunodeficiency virus, ARD = autoimmune rheumatic disease, HSCT = hematopoietic stem cell transplantation, SOT = solid organ transplantation, ICU = intensive care unit, HFNC = high-flow nasal cannula, CAPA = COVID-19-associated pulmonary aspergillosis.

Subgroup analysis of all-cause mortality at 28-days

As shown in Fig. 3, high-dose corticosteroid use significantly increased the mortality rate in patients who received respiratory support by nasal cannula or high-flow nasal cannula only, while there was no difference in mortality in patients receiving mechanical ventilation. In the subgroup analysis by comorbidities, an independent association was observed only in the population without underlying malignancies (Fig. 3). In all subgroups by age or sex, mortality at 28 days was higher in the high-dose corticosteroid group.

Fig. 3 Impact of high-dose corticosteroid on 28-day overall mortality in subgroups stratified by age, sex, comorbidities, and levels of respiratory support. The hazard ratio represents the risk of mortality associated with high-dose corticosteroid use in each subgroup.

HR = hazard ratio, CI = confidence interval, HFNC = high-flow nasal cannula, MV = mechanical ventilation.

Incidence and predictors of COVID-19-associated pulmonary aspergillosis

During hospitalization, 33 of 5,754 (0.6%) patients with COVID-19 were diagnosed with CAPA and 20 cases were included in the matched cohort. The IR of CAPA was 0.01 (95% CI, 0.00–0.02) per 100 patient days for the standard-dose group and 0.053 (95% CI, 0.03–0.08) for the high-dose matched control group. The cumulative incidence of CAPA in the high-dose corticosteroid group was significantly higher than that in the standard-dose group using the Kaplan-Meier method (3 of 2,138 [0.1%] vs. 17 of 2,138 [0.8%]; HR, 5.82; 95% CI, 1.71–19.86) (Fig. 4). The Fine and Gray regression model indicated a similar result but was not statistically significant (adjusted HR, 2.97; 95% CI, 0.94–9.43) (Table 3). A high level of respiratory support was the only independent predictor for the development of CAPA (Table 3).

Fig. 4 Cumulative incidence of COVID-19-associated pulmonary aspergillosis from the matched cohort, analyzed using the Kaplan-Meier method.

CAPA = COVID-19-associated pulmonary aspergillosis, HR = hazard ratio, CI = confidence interval.

Table 3 Multivariate Fine and Gray regression analysis of COVID-19-associated pulmonary aspergillosis development, with death considered as a competing risk

Variables	Fine and Gray univariate	Fine and Gray multivariate	
Crude HR	95% CI	P value	Adjusted HR	95% CI	P value	
Corticosteroid							
	Standard-dose	Reference			Reference			
	High-dose	5.87	1.71–20.17	0.004	2.97	0.94–9.43	0.065	
Age group, yr							
	< 60	Reference			Reference			
	60 ≤ age < 70	2.33	0.47–11.51	0.299	1.76	0.34–9.03	0.497	
	70 ≤ age < 80	2.55	0.54–12.08	0.238	1.71	0.34–8.66	0.518	
	≥ 80	1.49	0.29–7.67	0.632	1.06	0.20–5.74	0.943	
Sex (female vs. male)	0.68	0.28–1.68	0.406				
Household income							
	First percentile	Reference						
	Second percentile	1.07	0.26–4.45	0.922				
	Third percentile	0.57	0.11–2.94	0.573				
	Fourth percentile	1.54	0.53–4.48	0.426				
Degree of disability							
	None	Reference						
	Mild to moderate	0.76	0.18–3.20	0.703				
	Severe	0.71	0.24–4.61	0.947				
Smoking status							
	Never/former	Reference						
	Current	1.89	0.64–5.62	0.251				
BMI	0.87	0.80–0.94	< 0.001				
Creatinine	1.05	0.99–1.11	0.057				
Alcohol intake							
	Social drinker	Reference						
	Heavy drinker	0.80	0.10–6.13	0.825				
Hospital type							
	Referred	Reference						
	General	0.18	0.07–0.42	< 0.001				
Region of hospitals							
	Metropolitan area	Reference						
	Other	0.44	0.15–1.32	0.142				
Venous thrombosis	0.82	0.11–6.06	0.842				
Diabetes mellitus	1.99	0.67–5.93	0.215				
IHD/CHF	1.22	0.48–3.09	0.677				
COPD	1.57	0.60–4.10	0.353				
Tuberculosis	N/A						
CKD	1.15	0.27–4.97	0.849				
Stroke	1.47	0.61–3.55	0.397				
Dementia	N/A						
Solid cancer	1.42	0.42–4.82	0.576				
HMs	4.19	0.56–31.30	0.162				
HIV	N/A						
ARD	1.24	0.50–3.11	0.645				
HSCT	N/A						
SOT	N/A						
ICU admission	7.58	2.93–19.61	< 0.001				
Respiratory support							
	Nasal cannula	Reference			Reference			
	HFNC	11.35	3.17–40.64	< 0.001	8.11	2.33–28.20	0.001	
	Mechanical ventilation	11.97	2.98–48.15	< 0.001	7.65	1.95–29.97	0.003	
HR = hazard ratio, CI = confidence interval, BMI = body mass index, IHD = ischemic heart disease, CHF = congestive heart failure, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, HMs = hematologic malignancies, HIV = human immunodeficiency virus, ARD = autoimmune rheumatic disease, HSCT = hematopoietic stem cell transplantation, SOT = solid organ transplantation, ICU = intensive care unit, HFNC = high-flow nasal cannula.

Sensitivity analysis and exploratory results

In the sensitivity analysis conducted excluding patients who died within 7 days of hospitalization, the significant association of high-dose corticosteroid use with the risk of mortality was still observed (HR, 1.98; 95% CI, 1.66–2.36) (Supplementary Fig. 1). In addition, at 90 days from hospitalization, the high-dose group still showed a lower survival rate than the standard-dose corticosteroid group (HR, 1.63; 95% CI, 1.44–1.85) (Supplementary Fig. 2). A sub-analysis comparing the group with a daily dose of 5.5–6.0 mg from the standard-dose group to the group with doses > 12 mg from the high-dose group further showed that high-dose corticosteroid use remained associated with an elevated risk of mortality (HR, 2.84; 95% CI, 1.86–4.34) (Supplementary Fig. 3).

DISCUSSION

In this study, high-dose corticosteroid use increased all-cause mortality at 28 and 90 days after hospitalization in severe to critically ill patients with COVID-19. In particular, this association was significant in patients only requiring low- to high-flow nasal oxygen, and high-dose corticosteroid use did not result in better clinical outcomes, even in patients receiving mechanical ventilation. As a safety outcome, high-dose corticosteroid use showed a notable association with an increased risk of developing CAPA. However, CAPA itself did not independently affect overall mortality at 28 days.

Although administering 6 mg/day of dexamethasone for up to 10 days for severe COVID-19 is recommended, the clinical efficacy of using higher dose corticosteroids rather than the recommended dose has not been established.1428 In previous studies comparing high-dose corticosteroid use, a trend of mortality reduction and rapid recovery was observed.561129 However, there was a limitation that most of the study subjects were patients who used high levels of oxygen support due to severe respiratory failure. Furthermore, several retrospective and prospective studies have indicated that high-dose corticosteroid use was associated with an increase in all-cause mortality, and a meta-analysis did not show a benefit of high-dose corticosteroid use.89122930

To the best of our knowledge, this is the first study to analyze the real-world effects of high-dose corticosteroid use using nationwide data. In this study, the use of high-dose corticosteroids increased all-cause mortality at 28 and 90 days. These findings are consistent with previous trials that also showed harmful effects rather than improved outcomes.830 However, small study populations prevented previous studies from presenting risks according to severity or levels of respiratory support. Through subgroup analysis, we identified that mortality was significantly higher in patients who only received low- to high-flow nasal oxygen support. High-dose corticosteroid use was not associated with mortality benefit even in patients receiving mechanical ventilation in which improvement in prognosis was most expected. The mechanism behind increased mortality with high-dose corticosteroids is unclear, but it might be partially explained by delayed viral clearance and over-suppression of host immunity in a dose-dependent manner.831

Unintended consequences such as secondary infection due to corticosteroid use have continued to exist. Although prospective studies did not confirm the statistical significance between the use of systemic corticosteroids and the occurrence of CAPA, the limitation was that no CAPA-related diagnostic strategies were implemented in these clinical trials.3727 In contrast, several previous observational studies have suggested a statistical association between CAPA occurrence and systemic corticosteroid use.1527 In particular, the risk was significantly higher in the high-dose corticosteroid group than in the standard-dose group.1213 However, these results also had limitations, as they had different definitions of high-dose corticosteroid use and lacked statistical power due to the small number of patients developing CAPA.121332

In this study, we found that high-dose corticosteroid use showed a trend toward with an increased risk of CAPA development in severe to critically ill patients with COVID-19. The risk of CAPA was also significantly higher in intensive care unit (ICU) patients receiving high levels of respiratory support, which is consistent with previous studies.1227 Notably, the incidence of CAPA in this study was lower than that of previous studies conducted in Korea (11–12% in ICU patients).1213 This distinct difference is thought to be because previous studies included mostly tertiary-care hospitals that could diagnose CAPA with experienced medical staff and medical equipment. Whereas it is noteworthy to mention that this study comprised medical institutions that may have limited experience and diagnostic methods for diagnosing invasive fungal infections. In this regard, we strongly emphasize the importance of early diagnostic efforts through active surveillance and maintaining a high level of suspicion in patients with severe COVID-19 who are receiving high-dose corticosteroids, particularly those requiring high level of respiratory support.

This study had several limitations. First, the study period mainly included the epidemic periods from the wild type to the delta variant. This makes it difficult to assess the differences in survival and CAPA development according to different variants.33 Second, due to limitations in the claim data, covariates known to affect mortality and development of CAPA such as lymphopenia, Acute Physiology and Chronic Health Evaluation II score, and use of immunomodulating agents other than corticosteroids could not be adjusted for in the multivariate analysis and the matching variables.19343536 Lastly, it was not possible to completely rule out the use of anti-mold active agents for invasive aspergillosis that infrequently invaded organs other than the lung, or for invasive candidiasis when Echinocandin-based treatment was not feasible based on the operational definition of CAPA in this study.

In conclusion, high-dose corticosteroid use in severe to critically ill patients with COVID-19 significantly increased all-cause mortality at 28 and 90 days compared with the standard recommended dose. The risk of mortality was higher, especially in patients using low- and high-flow nasal oxygen. Although high-dose corticosteroid use and the severity of COVID-19 were notable predictors of CAPA, CAPA itself did not affect survival. This real-world evidence does not support the use of high-dose corticosteroids for severe to critically ill patients with COVID-19 regardless of levels of respiratory support and demonstrates the necessity of active surveillance for CAPA if a high-dose corticosteroid is used.

ACKNOWLEDGMENTS

We acknowledge the Department of Occupational and Environmental Medicine and Yun-Hee Lee for their consultation and statistical support for this study.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Operational definition of cohort variables

Supplementary Fig. 1

Kaplan-Meier analysis of 28-day all-cause mortality in a matched cohort, excluding patients with early hospital deaths.

Supplementary Fig. 2

Kaplan-Meier analysis of 90-day all-cause mortality in the matched cohort.

Supplementary Fig. 3

Kaplan-Meier analysis of 28-day all-cause mortality based on mean prescribed dexamethasone dosage (5.5–6.0 mg/day from standard-dose group vs. > 12 mg/day from high-dose group) in a matched cohort.

Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1I1A1A01070887).

Disclosure: The authors have no potential conflicts of interest to disclose.

Data Availability Statement: The datasets were derived from sources in the public domain: National Health Insurance Service (NHIS) of South Korea, https://nhiss.nhis.or.kr.

Author Contributions: Conceptualization: Lee R, Cho SY, Lee DG.

Data curation: Lee R, Nho D.

Formal analysis: Lee R, Cho SY, Nho D.

Funding acquisition: Lee R.

Investigation: Lee R.

Methodology: Lee R, Cho SY, Nho D, Lee DG.

Project administration: Lee R, Lee DG.

Supervision: Cho SY, Lee DG.

Writing - original draft: Lee R.

Writing - review & editing: Cho SY, Nho D, Lee DG.
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