Use of glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19.

OBJECTIVE: To describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia, based on the potential benefit of the non-genomic mechanism of these drugs at higher doses.
METHODS: Observational study using data collected from the SEMI-COVID-19 Registry. We evaluated the epidemiological, radiological and analytical scenario between patients treated with megadoses therapy of corticosteroids vs low-dose of corticosteroids and the development of complications. The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses.
RESULTS: Of a total of 14,921 patients, corticosteroids were used in 5,262 (35.3%). Of them, 2,216 (46%) specifically received megadoses. Age was a factor that differed between those who received megadoses therapy versus those who did not in a significant manner (69 years [IQR 59-79] vs 73 years [IQR 61-83]; p < .001). Radiological and analytical findings showed a higher use of megadoses therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91-2.24 p < .001) and megadose use with increased survival (OR 0.84 95% CI 0.75-0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32-1.80; p < .001). There is no difference between megadoses and low-dose (p .298). Although, there are differences in the use of megadoses versus low-dose in terms of complications, mainly infectious, with fewer pneumonias and sepsis in the megadoses group (OR 0.82 95% CI 0.71-0.95; p < .001 and OR 0.80 95% CI 0.65-0.97; p < .001) respectively.
CONCLUSION: There is no difference in mortality with megadoses versus low-dose, but there is a lower incidence of infectious complications with glucocorticoid megadoses.

Introduction

On December 31st, 2019, Wuhan Municipal Health and Sanitation Commission (Hubei Province, China) reported 27 new cases of pneumonia of an unknown etiology to the World Health Organization. The agent causing this pneumonia has been identified as a virus of the Coronaviridae family, named SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) [1,2].

It has been postulated that in the development of the disease it is possible to distinguish a hyper-inflammatory phase, in which using glucocorticoids might play an essential role in preventing acute pulmonary distress syndrome (ARDS) [3-5].

Corticosteroids (CS) have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large.

The aim of this study is to describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia.

Literature search

A literature search was conducted using the MEDLINE database with the following search terms: “corticosteroids and COVID-19,” “megadoses and SARS-CoV-2,” and “immunomodulatory and COVID-19.” The most up-to-date evidence and all information regarding use of corticosteroids in COVID-19 reported in English or Spanish were selected.

Material and methods

This work is a multicenter, nationwide, observational study based on patient data obtained from the SEMI-COVID-19 Registry, an enterprise of the Spanish Society of Internal Medicine (SEMI, for its initials in Spanish) to advance knowledge of the patients infected with SARS-CoV-2. The SEMI-COVID-19 Registry was approved by the Provincial Research Ethics Committee of Málaga (Spain).

Study design and population

The registry is an anonymized online database of retrospective data on consecutive adult patients with COVID-19 hospitalized in internal medicine departments from 131 Spanish hospitals. The diagnosis was confirmed microbiologically by reverse transcription polymerase chain reaction (RT-PCR) testing of a nasopharyngeal or bronchoalveolar lavage sample. Exclusion criteria were subsequent admissions of the same patient and denial or withdrawal of informed consent. Patients were cared for at their attending physician’s discretion, according to local protocols and their clinical judgment.

The registry includes data on more than 300 variables in categories such as:

Sociodemographic and epidemiological data

Personal medical and medication history

Symptoms and physical examination findings upon admission

Laboratory test results

Radiological findings and their progress

Pharmacological treatment and ventilatory support

In-hospital complications and causes of death

More in-depth information on the registry and preliminary results are available in a previously published work [6].

Study endpoints

The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses, defined as > 150 mg of prednisone in 24h. The follow-up period was from admission to discharge or death, including early readmissions.

We analyzed the criteria for the use of megadoses, any relationship to epidemiological, clinical, laboratory, and radiologic parameters, and the development of complications depending on the use of megadoses of corticosteroids.

Data analysis

We initially selected patients who received corticosteroids (5,262 out of a sample of 14,921). We further subdivided this population into two groups according to the amount of corticosteroids received: low-dose and megadoses. We defined megadoses therapy as the use of > 150 mg prednisone in 24h.

Continuous quantitative variables were tested for normal distribution using rates of skewness and kurtosis, Levene’s test, or the Kolmogorov-Smirnov test, as appropriate. These variables were expressed as medians and interquartile range (IQR). Comparisons between groups were made using the Student’s T-test, Mann-Whitney U test, Wilcoxon test, analysis of variance (ANOVA), or the Kruskal-Wallis test. Categorical variables were expressed as absolute values and percentages. Differences in proportions were analyzed using the chi-square test, McNemar’s test, or Fisher’s exact test, as appropriate.

Measures of association were expressed as odds ratio (OR) with 95% confidence intervals (95% CI). Statistical analysis was carried out using STATA software (v14.2). Statistical significance was established as p < 0.005.

We also used logistic regression to evaluate the relationship between use of megadoses and mortality. A multivariate analysis was carried out to adjust for confounding variables using clinically relevant, statistically significant variables (p < 0.001) identified in the previous analysis.

Results

Demographics, and clinical features

Demographics and comorbidities in patients with corticosteroids or megadose therapy are shown in Table 1. Age differed between those who received megadose therapy versus those who did not in a significant manner (69 years [IQR 59–79] vs 73 years [IQR 61–83]; p < .001). There was a lower rate of megadose therapy among patients with dyslipidemia, arterial hypertension, heart and respiratory diseases. Regarding patients’ previous treatment, a lower percentage of patients who were taking systemic corticosteroids therapy or other immunosuppressive received megadoses therapy.

Table 1

Demographics and comorbidities.

	Total population (n = 14,921) 1					Population with CS used (n = 4794) 2
	N	No. (%)	NO CS (n = 9,659)	WITH CS (n = 5,262)	P value 1	N	Low-dose CS (n = 2,578) No (%)	CS Megadoses (n = 2,216) No (%)	P value 2
Median [range], Age (years)	14,921	69.33 [56.34–79.9]	67.5 [53.95–79.23]	71.71 [60.14–80.97]	<0.001	4,794	73.79 [61.41–83.41]	69.78 [59.29–79.10]	<0.001
Age groups:					<0.001				<0.001
< 40 years		927 (6.2)	754 (7.8)	173 (3.3)			79 (3.1)	71 (3.2)
40–50 years		1,433 (9.6)	1,083 (11.2)	350 (6.7)			148 (5.7)	165 (7.5)
50–60 years		2,385 (16.0)	1,614 (16.7)	771 (14.7)			340 (13.2)	354 (16.0)
60–70 years		2,923 (19.6)	1,822 (18.9)	1,101 (20.9)			473 (18.4)	534 (24.1)
70–80 years		3,570 (23.9)	2,135 (22.1)	1,435 (27.3)			700 (27.2)	603 (27.2)
> 80 years		3,683 (24.7)	2,251 (23.3)	1,432 (27.2)			838 (32.5)	489 (22.1)
Gender:	14,906				<0.001	4,788			<0.001
Women		6,375 (42.8)	4,443 (46.0)	1,932 (36.8)			1,044 (40.6)	730 (33.0)
Men		8,531 (57.2)	5,208 (54.0)	3,323 (63.2)			1,530 (59.4)	1,484 (67.0)
Race:	14,678				<0.001	4,708			0.43
Caucasian		13,254 (90.3)	8,527 (89.7)	4,727 (91.4)			2,316 (91.7)	1,988 (91.1)
African American		54 (0.4)	33 (0.4)	21 (0.4)			12 (0.5)	8 (0.4)
Latin		1,182 (8.1)	822 (8.7)	360 (7.0)			167 (6.6)	162 (7.4)
Asian		63 (0.4)	47 (0.5)	16 (0.3)			5 (0.2)	9 (0.4)
Other		125 (0.9)	79 (0.8)	46 (0.9)			25 (1.0)	16 (0.7)
Arterial hypertension	14,899	7,573 (50.8)	4,590 (47.6)	2,983 (56.8)	<0.001	4,789	1,531 (59.5)	1,215 (54.9)	0.001
Type 2 diabetes mellitus	14,876	2,864 (19.3)	1,724 (17.9)	1,140 (21.7)	<0.001	4,791	573 (22.2)	476 (21.5)	0.54
Dyslipidaemia	14,890	5,902 (39.6)	3,630 (37.7)	2,272 (43.3)	<0.001	4,783	1,169 (45.5)	908 (41.1)	0.002
Obesity (BMI>30)	13,573	2,866 (21.1)	1,657 (18.8)	1,209 (25.4)	<0.001	4,344	583 (25.1)	539 (26.7)	0.23
Smoking status:	14,227				<0.001	4,548			0.29
Never		9,859 (69.3)	6,626 (71.7)	3,233 (64.8)			1,585 (64.3)	1,376 (66.1)
Formed		3,613 (25.4)	2,128 (23.0)	1,485 (29.8)			757 (30.7)	594 (28.5)
Current		755 (5.3)	486 (5.3)	269 (5.4)			123 (5.0)	113 (5.4)
Atrial fibrillation	14,881	1,663 (11.2)	1,040 (10.8)	623 (11.9)	0.044	4,778	349 (13.6)	218 (9.9)	<0.001
Myocardial infarction	14,886	1,188 (8.0)	703 (7.3)	485 (9.2)	<0.001	4,787	259 (10.1)	186 (8.4)	0.049
Hearth failure	14,893	1,071 (7.2)	637 (6.6)	434 (8.3)	<0.001	4,787	259 (10.1)	133 (6.0)	<0.001
COPD	14,893	1,021 (6.9)	505 (5.2)	516 (9.8)	<0.001	4,784	302 (11.7)	168 (7.6)	<0.001
Chronic bronchitis	14,891	746 (5.0)	416 (4.3)	330 (6.3)	<0.001	4,787	199 (7.7)	105 (4.8)	<0.001
Asthma	14,888	1,079 (7.3)	652 (6.8)	427 (8.1)	0.002	4,789	235 (9.1)	153 (6.9)	0.005
Obstructive Sleep Apnea Syndrome	14,825	884 (6.0)	494 (5.1)	390 (7.5)	<0.001	4,768	184 (7.2)	176 (8.0)	0.29
Dementia	14,890	1,496 (10.1)	994 (10.3)	502 (9.6)	0.14	4,788	335 (13.0)	135 (6.1)	<0.001
Stroke	14,873	1,081 (7.3)	664 (6.9)	417 (7.9)	0.019	4,782	235 (9.2)	151 (6.8)	0.003
Neurodegenerative disease	14,897	1,356 (9.1)	869 (9.0)	487 (9.3)	0.59	4,784	316 (12.3)	142 (6.4)	<0.001
Cancer	14,878	1,241 (8.3)	787 (8.2)	454 (8.6)	0.32	4,787	234 (9.1)	183 (8.3)	0.32
Leukaemia	14,903	179 (1.2)	93 (1.0)	86 (1.6)	<0.001	4,791	43 (1.7)	37 (1.7)	0.99
Lymphoma	14,892	212 (1.4)	120 (1.3)	92 (1.8)	0.013	4,789	45 (1.8)	35 (1.6)	0.65
HIV infection	14,861	102 (0.7)	73 (0.8)	29 (0.6)	0.15	4,779	17 (0.7)	11 (0.5)	0.46

CS = Corticosteroids, BMI = Body Mass Index, COPD = Chronic Obstructive Pulmonar Disease, HIV = Human Inmunodefiency Virus.

1: Bivariate analysis with the total population, hypothesis testing according to the use or not of corticosteroids.

2: Bivariate analysis only with patients in whom corticosteroids were used and we have information on the use of megadoses, hypothesis testing according to the use or not of megadoses of corticosteroids.

Laboratory and radiologic findings

Radiologic and laboratory findings showed a higher use of megadose therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19, such as elevated lactate dehydrogenase and C-reactive protein, on admission. Full data are presented in Table 2.

Table 2

Use of megadoses according to analytical parameters and radiological findings on admission.

	NO CS		Low-dose CS		CS Megadoses		P Value	P Value 1
	No.	Mean (SD)	No.	Mean (SD)	No.	Mean (SD)		A vs B	A vs C	B vs C
Haemoglobin (g/dL)	10,042	13.72 (1.86)	2,566	13.50 (2.0)	2,209	13.83 (1.92)	<0.001	<0.001	0.007	<0.001
Platelets (x 10^6/L)	10,047	207.428(92.308)	2,563	201.961(90.659)	2,203	210.757 (96.110)	0.001	0.001	0.597	0.003
Leukocytes (x 10^6/L)	1,040	7137 (5283)	2,566	7917(5807)	2,209	7837 (6077)	<0.001	<0.001	<0.001	0.259
Neutrophils (x 10^6/L)	9,987	5262 (4627)	2,558	6125 (4501)	2,201	6030 (4472)	<0.001	<0.001	<0.001	0.622
Lymphocytes (x 10^6/L)	10,026	1182 (1981)	2,561	1156 (2695)	2,206	1117 (2362)	<0.001	<0.001	<0.001	0.754
CPR (mg/L)	9,699	76.65 (83.64)	2,459	105 (93.55)	2,137	114.2 (96.73)	<0.001	<0.001	<0.001	<0.001
Procalcitonin (ng/mL)	4,625	0.4341(2.353)	1,312	0.6354 (2.361)	1,112	0.4706 (1.991)	<0.001	<0.001	<0.001	0.230
Lactate dehydrogenase (U/L)	8,654	355.7 (207.6)	2,208	390.1 (214)	2,023	419.9 (284.4)	<0.001	<0.001	<0.001	<0.001
Interleukin-6 (pg/mL)	1,146	54.92 (160.4)	3,57	82,57 (158,1)	4,65	91.65 (218.9)	<0.001	<0.001	<0.001	0.386
D-dimer (ng/mL)	7,631	1643 (7960)	2,034	2458 (12445)	1,963	2417 (11879)	<0.001	<0.001	<0.001	0.267
	N	No (%)	N	No (%)	N	No (%)
Condensation	9,988	4,753 (47.6)	2,544	1,298 (51.0)	2,207	1,152 (52.2)	<0.001	0.002	<0.001	0.432
Interstitial infiltrate	9,989	6,050 (60.6)	2,552	1,617(63.4)	2205	1570 (71.2)	<0.001	0.010	<0.001	<0.001
Pleural effusion	9,979	458 (4.6)	2,553	137 (5.4)	2,206	89 (4)	<0.001	0.106	0.280	0.034

CPR = C-reactive protein, CS = Costicosteroids, SD = Standard Desviation.

1: P-value of the hypothesis test for subgroups. Mann Whitney U or Fisher’s exact test was used as appropriate.

Groups A: No CS; B: Low-dose CS; C: CS-Megadoses.

Other treatments

In Table 3 we studied the use of other treatments concomitantly for SARS-CoV-2 infection. There was a trend towards greater use of other immunomodulatory medications in those patients who also received corticosteroid megadoses.

Table 3

Other immunomodulatory therapies used in patients with CS.

	WITH CS No. (Total n = 5,262)	Low-dose CS (n = 2,578)No (%)	CS Megadoses (n = 2,216)No (%)	P value
Use of lopinavir-ritonavir	3,082 (4,784)	1,499 (58.3)	1,583 (71.5)	<0.001
Use of hidroxychloroquine	4,284 (4,789)	2,260 (87.7)	2,024 (91.5)	<0.001
Use of beta-interferon 1B	669 (4,768)	376 (14.7)	293 (13.3)	0.17
Use of tocilizumab	842 (4,775)	325 (12.7)	517 (23.5)	<0.001
Use of anakinra	82 (4,751)	17 (0.7)	65 (3.0)	<0.001
Use of remdesivir	38 (4,755)	24 (0.9)	14 (0.6)	0.25
Use of chloroquine	213 (4,765)	79 (3.1)	134 (6.1)	<0.001
Use of immunoglobulins	53 (4,725)	12 (0.5)	41 (1.9)	<0.001
Use of baricitinib	86 (3,929)	15 (0.7)	71 (3.8)	<0.001
Use of colchicine	67 (4,732)	40 (1.6)	27 (1.2)	0.31
Use of inhaled beclomethasone	355 (4,746)	191 (7.5)	164 (7.5)	0.98

CS = Corticosteroids.

Complications and mortality

There are differences in the use of megadoses versus low-dose in terms of complications. This is reflected in Table 4. The risk of most complications was lower in the group of megadoses, especially those related to other infections (bacterial pneumonia OR 0.82, 95% CI 0.71–0.95; p .010 and sepsis 0.80 (0.65–0.97) OR 0.80, 95% CI 0.65–0.97; p .026). Although the risk was only higher in the case of stroke (OR 2.60, 95% CI 1.38–4.90; p .003, or venous thromboembolic disease (OR 1.72, 95% CI 1.26–2.33 p .001).

Table 4

Development of complications in patients with CS.

	WITH CS No. (Total n = 5,262)	Low-dose CS (n = 2,578) No (%)	CS Megadoses (n = 2,216) No (%)	Odds ratio (IC 95%)	P value
Heart failure	4,789	256 (9.9)	132 (6.0)	0.57 (0.46–0.72)	<0.001
Cardiac arrhytmia	4,787	171 (6.6)	113 (5.1)	0.76 (0.59–0.97)	0.026
Epileptic seizure	4,790	23 (0.9)	13 (0.6)	0.66 (0.33–1.30)	0.23
Stroke	4,787	14 (0.5)	31 (1.4)	2.60 (1.38–4.90)	0.003
Acute renal failure	4,786	542 (21.1)	401 (18.1)	0.83 (0.72–0.96)	0.010
Venous thromboembolic disease	4,781	72 (2.8)	104 (4.7)	1.72 (1.26–2.33)	0.001
Acute peripheral arterial disease	4,765	17 (0.7)	16 (0.7)	1.09 (0.55–2.17)	0.80
Disseminated intravascular coagulation	4,782	40 (1.6)	43 (2.0)	1.26 (0.81–1.94)	0.30
Bacterial pneumonia	4,784	487 (18.9)	356 (16.1)	0.82 (0.71–0.95)	0.010
Sepsis	4,785	260 (10.1)	182 (8.2)	0.80 (0.65–0.97)	0.026
Shock	4,776	203 (7.9)	142 (6.4)	0.80 (0.65–1.01)	0.051
Multiorgan failure	4,782	223 (8.7)	180 (8.2)	0.93 (0.76–1.15)	0.52

CS = Corticosteroids.

The analysis of outcome and mortality is shown in Table 5. We found no difference between ICU admission (14.4% low dose; 15% megadoses p .54) and average in hospital stay per days in both groups (12 days, IQR 7–18 low-dose; 12 days, IQR 8–19 megadoses. p .88).

Table 5

Outcome according to the use of megadoses.

	WITH CS No. (Total n = 5,262)	Low-dose CS (n = 2,578) No (%)	CS Megadoses (n = 2,216) No (%)	Odds ratio (IC 95%)	P value
Hospital stay in days, median (IQR)	4,794	12 (7–18)	12 (8–19)	0.99 (0.99–1.01)	0.88
High-flow nasal cannula	4,767	325 (12.7)	340 (15.4)	1.25 (1.06–1.47)	0.008
Non-invasive mechanical ventilation	4,778	214 (8.3)	243 (11.0)	1.36 (1.12–1.65)	0.002
Invasive mechanical ventilation	4,782	307 (12.0)	250 (11.3)	0.94 (0.79–1.12)	0.49
Prone position	4,774	413 (16.1)	586 (26.6)	1.89 (1.64–2.17)	<0.001
ICU admission	4,793	370 (14.4)	332 (15.0)	1.05 (0.90–1.23)	0.54
Resolution of first episode
Discharge home	4,794	1,656 (64.2)	1,509 (68.1)	1 (ref.)	-
Convalescence centre		139 (5.4)	108 (4.9)	0.85 (0.66–1.11)	0.23
Death during hospital admission		783 (30.4)	599 (27.0)	0.84 (0.74–0.95)	0.007
Readmission to hospital
Readmission	4,630	130 (5.2)	75 (3.5)	0.66 (0.49–0.88)	0.005
Days of discharge to readmission, median (IQR)	205	8.5 (2–16)	12 (5–15)	1.02 (0.99–1.05)	0.12
Mortality 1	4,750	803 (31.4)	608 (27.7)	0.84 (0.74–0.95)	0.005

ICU = Intensive care unit, CS = Corticosteroids.

1: Death at any time. Either on first admission, on discharge or on re-admission.

Tables 6 and 7 show the relationship between steroid use and mortality. Patients were initially divided into two groups according to whether or not they received steroid therapy, and specifically the use of megadoses or low-dose of corticosteroids. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91–2.24 p <0.001) and megadose use with increased survival (OR 0.84 95% CI 0.75–0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32–1.80; p < .001). The low-dose corticosteroid group it is also associated with higher mortality (OR 1.40, 95% CI 1.21–1.61; p < .001). There is no difference in mortality between megadoses and low-dose (p .298).

Table 6

Corticosteroids therapy and mortality.

	No. (Total n = 14,921)	No. (%)	SURVIVORS (n = 11,862)	DECEASED (n = 3,059)	Odds ratio (IC 95%)	P value
Use of systemic corticosteroids	5,262	35.3	3,763 (31.7)	1,499 (49)	2.07 (1.91–2.24)	<0.001
Use of CS Megadoses	2,216	46.2	1617 (47.4)	599 (43.3)	0.84 (0.75–0.96)	0.011
Days from sympton onset to start of corticosteroids
< 10 days	5,023	2,719 (54.1)	1,783 (49.5)	936 (65.9)	1 (ref.)	-
> 10 days		2,304 (45.9)	1,820 (50.5)	484 (34.1)	0.51 (0.45–0.58)	<0.001
Other immunomodulatory therapies used in patients with CS
Use of lopinavir-ritonavir	9,148	61.4	1599 (52.4)	7549 (63.7)	0.63 (0.58–0.68)	<0.001
Use of hidroxychloroquine	12,772	85.7	10487 (88.5)	2285 (74.7)	0.34 (0.35–0.43)	<0.001
Use of tocilizumab	1,257	8.4	948 (8)	309 (10.1)	1.294 (1.13–1.48)	<0.001
Use of baricitinib	92	0.8	80 (0.9)	12 (0.5)	0.5707 (0.31–1.04)	0.071
Other treatment strategies employed
High-flow nasal cannula	1,189	8	767 (6.5)	422 (13.9)	2.32 (2.04–2.63)	<0.001
Non-invasive mechanical ventilation	719	4.8	351 (3)	368 (12.1)	4.5 (3.86–5.23)	<0.001
Invasive mechanical ventilation	975	6.6	535 (4.5)	440 (14.4)	3.56 (3.12–4.07)	<0.001
Prone position	1,519	10.2	854 (7.2)	665 (21.9)	3.6 (3.2–4.01)	<0.001
ICU admission	1,218	8.2	737 (6.2)	481 (15.7)	2.8 (2.5–3.2)	<0.001

ICU = Intensive care unit, CS = Corticosteroids.

Table 7

Megadoses and mortality (multivariate analysis adjusted according to patient age, comorbidities and other treatments).

	Odds ratio (IC 95%)	P value
Corticosteroids therapy
No CS	1 (ref.)	-
Low-dose CS	1.40 (1.21–1.61)	<0.001
CS Megadoses	1.54 (1.32–1.80)	<0.001
Age	1.09 (1.09–1.10)	<0.001
Sex (women)	0.59 (0.52–0.66)	<0.001
Arterial hypertension	1.21 (1.07–1.37)	0.002
Dyslipidaemia	1.08 (0.97–1.21)	0.145
Atrial fibrillation	1.2 (1.03–1.40)	0.017
Hearth failure​	1.47 (1.22–1.77)	<0.001
COPD	1.28 (1.07–1.54)	0.07
Stroke	1.25 (1.05–1.48)	0.012
Dementia	1.30 (1.05–1.61)	0.015
Neurodegenerative disease	1.33 (1.07–1.66)	0.010
Use of lopinavir-ritonavir	0.99 (0.88–1.12)	0.93
Use of hydroxychloroquine	0.50 (0.43–0.57)	<0.001
Use of tocilizumab	0.62 (0.49–0.80)	<0.001
Use of baricitinib	0.34 (0.16–0.71)	0.005
High-flow nasal cannula	1.73 (1.41–2.11)	<0.001
Non-invasive mechanical ventilation	4.01 (3.17–5.07)	<0.001
Invasive mechanical ventilation	5.32 (3.16–8.98)	<0.001
Prone position	3.33 (2.71–4.08)	<0.001
ICU admission	0.68 (0.41–1.45)	0.151

ICU = Intensive care unit, CS = Corticosteroids, COPD = Chronic Obstructive Pulmonar Disease.

In addition, when analyzing the relationship with mortality, patients who received lopinavir-ritonavir (OR 0.65, 95% CI 0.58–0.74; p < .001), hydroxychloroquine (OR 0.53, 95% CI 0.44–0.63; p < .001) and tocilizumab (OR 0.84, 95% CI 0.71–0.98; p .029), among others, had a higher survival rate.

Discussion

Throughout these long months of the covid19 pandemic, there has been much controversy about the role of corticosteroids in covid19 pneumonia, as there was no evidence of benefit in previous similar viral infections [5]. In March 2020, the World Health Organization (WHO) advised against its use [7], however the results of the RECOVERY clinical trial showed a reduction in mortality in the patients treated with 10 days of dexamethasone 6 mg compared to the placebo group [8].

To begin with, it is worth highlighting in this study the high number of patients who received corticosteroids. Specifically, 2216 out of 4794 patients received megadoses, considering megadose an amount of prednisone greater than 150 mg per day [9], representing a 46% in comparison with the 40% of people receiving pulse therapy in the Irastorza et al. observational study of 242 patients [10], and the 20% described in the one published by López Zuñiga with 318 participants [11].

The particular interest in evaluating the difference between megadoses in contrast to lower doses was based on the hypothesis that they could have different impact on the evolution of the disease, as well as different side effects, since pulse therapy uses the non-genomic mechanisms of glucocorticoids to enhance the anti-inflammatory power and reduce the metabolic side effects and incidence of infections [12], as it has been demonstrated in other systemic autoimmune diseases [13].

Even though the advanced age, hypertension and dyslipidemia were postulated as risk factors for ADRS [14], in our work the patients receiving megadoses were younger and suffered less comorbidities than the patients of the other group, in contrast to the Irastorza series [10] in which no significant differences were observed. However, in his study, patients who received pulse therapy out of the second week of the disease and patients who did not receive corticosteroids were included in the same group. Returning to our study, a significant greater number of men received megadoses compared to women, 67% vs 33% respectively, perhaps because of the serious incidence of ADRS in men and their worse prognosis compared to women [15].

It should also be noticed that patients receiving previous immunosuppressive therapy received lower proportion of megadoses; we could not know if this was due to the fear of viral persistence already described in immunocompromised hosts [16], or because of a milder course in these patients, as current evidence only shows a probably increased risk of severe COVID-19 and death in patients with malignancy or solid organ transplant recipients, but this is less clear in other immunocompromised patients [17].

As for the situation at admission, the patients receiving megadoses had significant higher levels of lactate-dehydrogenase, c-reactive-protein and D-Dimer in contrast to the low-dose group, considering the higher these inflammatory markers are, the more they have been associated with lung damage, ADRS and worse prognosis. We found similar results about the radiological scenario, since the people treated with megadoses had a significant interstitial infiltrate in the X ray at admission in comparison with the low-dose group, and the radiological extension has also been associated to ADRS [18].

Regarding concomitant use with other immunomodulatory treatments or adjunctive treatments such us lopinavir-ritonavir, the group of patients of megadoses treatment received also more lopinavir-ritonavir, tocilizumab and bariticinib. A sub-analysis in our study of their effect on mortality showed that patients on lopinavir-ritonavir survived longer, as did those on tocilizumab and bariticinib. In this sense, it was hypothesized whether the concomitant effect of both, megadoses of corticosteroids and the specific immunomodulator, may influence the survival of COVID-19 patients. On tocilizumab, the EMPACTA clinical trial [19] included 249 patients in the tocilizumab group and 128 patients in the placebo group and the results suggested that patients who were most likely to benefit from tocilizumab had moderate or severe disease and that tocilizumab may add a potential benefit to antiviral treatment and glucocorticoids. Concerning bariticinib, there are few studies reflecting its use and impact on covid-19 and they include few patients. [20,21] In our study there were 86 cases registered who received corticosteroids at the same time, mostly megadoses, with a protective effect on mortality which is an interesting finding that requires further study. As for lopinavir-ritonavir, a randomized trial found that this treatment added to standard supportive care was not associated with clinical improvement or mortality in seriously ill patients with COVID-19 compared to standard care alone [22].

As for the development of complications during admission, significantly more complications of heart failure, arrhythmias and renal failure were observed in the non-megadose group, probably influenced by the higher proportion of comorbidities observed in this group compared to the megadose group. On the other hand, the incidence of venous thromboembolic disease and stroke in patients who used megadoses was higher, maybe explained by the greater inflammation in these patients, as it has been demonstrated in other studies [23,24]. In other series, there have been reported a 7% of bacterial coinfections in hospitalized COVID-19 patients, increasing to 14% in studies that only included ICU patients [25]. We would like to highlight that no higher proportion of bacterial pneumonia or sepsis were observed in the megadose group, supporting the initial hypothesis on the use of the non-genomic pathway of megadoses, as explained earlier [12].

Regarding the evolution of the patients who received corticosteroids, no increase in the average hospital stay was described among those who used megadoses. The patients in the megadoses group required more high-flow devices and non-invasive mechanical ventilation, but there were no differences between groups in terms of transfers to ICU or invasive ventilation.

In the observational study of Fernandez Cruz et al, a significant reduction in mortality was demonstrated among glucocorticoids users in the group classified as moderate-severe disease, but there were not significant differences between the patients receiving 1 mg/kg/d of methylprednisolone or pulse therapy (up to 500mg/d) [26]. In this study, the preliminary bivariate analysis showed an increased mortality among the patients receiving corticosteroids, however, in the group treated with megadoses (OR 0.85 CI 0.75–0.96) the survival rate was higher compared to the no megadoses group. The statistical significance disappeared in the multivariate analysis due to the introduction of confounding factors. Increased mortality is observed in the megadose group, as opposed to this type of regimen in other systemic autoimmune diseases [13]. Several studies have been recently published showing the effectiveness of high dose glucocorticoid pulse therapy in the prognosis of patients with COVID19 pneumonia in the inflammatory stage of the disease [10,11,27] in contrast to a Brazilian double-blind, randomized, placebo-controlled trial which reported no benefit from the use of methylprednisolone [28].

Thus, there is still no clear answer to which dose should be used, how long it should last or even if there are significant differences between dexamethasone and methylprednisolone. A new randomized controlled trial (CORTIVID) is coming soon with the intention to evaluate the role of pulse therapy [29].

Conclusion

This study includes a huge number of patients treated with corticosteroids and specifically with megadoses. There is no difference in mortality with megadoses versus low-dose of corticosteroids, but there is a lower incidence of infectious complications in megadoses group.

Limitations

It is a retrospective study. We could not evaluate the impact of megadoses in the respiratory situation, radiological evolution, nor in the inflammatory parameters, as we only had the data at the moment of hospital admission and a week later, so we could not establish a direct relationship with the glucocorticoid treatment, since it is difficult to establish the temporal relationship between the evolution of the evolution of the clinical parameters and the treatment. Besides, although the treatment regimens were divided into megadoses vs low-dose of corticosteroids based on > 150mg of prednisone/day or <150mg/day respectively, we could not establish the exact treatment regimens, the type of glucocorticoid used, nor its duration. Moreover, there are other glucocorticoid-related infections and side effects that have not been evaluated in this registry, so further studies and specific clinical trials to evaluate the differences between regimens are needed.

Statistical results.

(DOCX)

Click here for additional data file.

(DOCX)

Click here for additional data file.

21 Jul 2021

PONE-D-21-21800

Use of Glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19.

PLOS ONE

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Reviewers' comments:

Reviewer #1: The authors present their experience with high-dose corticosteroids (CS), referred to as megadoses, and compare these against low-dose CS.

Intro, paragraph 2: consider rephrasing in order to be current with the literature. CS are the only intervention for severe COVID with consistent mortality impact across studies. I would avoid using the references 5-7 that raised controversies in CS use too early in the pandemic and based on theoretical assumptions from non-COVID diseases such as ARDS, SARS or MERS that have distinct etiology, epidemiology, phenotypes and outcomes. Instead, you can highlight even though CS have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large.

Methods: Study conclusion: consider renaming this section Study endpoints to avoid confusion with the use of the word conclusion. The Literature search section does not add to the methods, consider removing.

There are 2 definitions of megadoses, >150 mg of prednisone in 3-4 days and >150 mg of prednisone in 24h. Historically, high-dose CS in ARDS research has been defined as >200mg/Kg/day of methylprednisolone or its equivalent in other CS forms (prednisone, prednisolone, etc). If the authors choose to study >150mg of prednisone then I would recommend using the definition of >150mg in 24h and report the cumulative dose of steroids AND the daily dose in a "mg/Kg/day" format to keep up to the literature.

Results: Overall the results are focused on all patients receiving CS vs those who didn't, and then in CS megadoses vs no megadoses. I believe it would be more useful to change to 3 groups in the tables: No CS, low-dose CS and CS megadoses.

Table 2 is too long, try grouping comorbidities to clinically relevant terms that are well known risk factors for COVID, such as chronic lung disease, chronic cardiovascular disease, renal insufficiency, etc. Table 1 can be integrated at the end of table 2 as it does not add much as a stand-alone table. Revise spelling in the tables.

For table 4 and 5 it would be more useful merged to have the mean/median of lab values instead of the proportion of abnormal labs in both groups as this can be misleading. Table 7 would be more useful if describing megadoses vs regular steroids. Consider adding APACHE, PaFiO2, or other proxies to clinical status upon admission.

There are higher inflammatory markers in patient's receiving megadoses according to tables 4 and 5, this creates an uneven populations to compare the effect of megadoses. There are 2 ways to address this unbalance: inverse weight proportion analysis and propensity-score matching. Consider using one of these to strengthen results.

Mortality metric used in too broad including follow-up of patients already discharged, with a median hospital stay of 12 days, using 30-day mortality would be preferred.

Reviewer #2: From my point of view, it is of little interest to focus the study on the differences between patients who have received megadoses and those who have not. It is much more interesting to find out if the megadoses had negative consequences, in terms of complications, hospital stay or mortality.

Most of the conclusions drawn by the authors are based on bivariate analyzes, which in an observational study like this one, have no more value than merely descriptive. As the authors note, there are a large number of important differences between patients treated with megadoses and those who are not, so the results in terms of complications or mortality are very difficult to interpret. The authors carry out a single multivariate analysis on mortality, in which they have only introduced a few, of the many factors that they have found asymmetrically distributed between groups, without providing an explanation of the selection process carried out. That is, there are enough confounding factors missed in the analysis, so the results most likely have residual confusion. In addition, some important confounding factors that can affect health outcomes in COVID-19 do not seem to have been available, such as saturation and the rest of vital signs, respiratory support, etc. Also, Multivariate analysis, which is essential in this type of observational studies, is limited to mortality results, and has not been done for other interesting results such as, for example, complications of the disease.

Unfortunately, I do not believe that the results are valid for the outcomes of greatest interest, due to the lack of control for relevant confounders, so I cannot recommend the publication in its current state. However, the authors have a valuable database, and their idea of comparing the effect of high doses with other doses of steroids is interesting. I encourage them to choose a relevant outcome, such as mortality, and do a full multivariate analysis, which attempts to elucidate whether mega-doses are associated with higher mortality. They also have an exceedingly large sample, to match patients in whom megadoses were used, with controls with similar clinical characteristics, in which megadoses were not used. In short, they have many possibilities with this database, and I am sure they can make a much more robust analysis than the one presented here, to provide new knowledge about corticosteroids effect in this disease.

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4 Dec 2021

Response to Reviewers:

Reviewers' comments:

Reviewer #1: The authors present their experience with high-dose corticosteroids (CS), referred to as megadoses, and compare these against low-dose CS.

Intro, paragraph 2: consider rephrasing in order to be current with the literature. CS are the only intervention for severe COVID with consistent mortality impact across studies. I would avoid using the references 5-7 that raised controversies in CS use too early in the pandemic and based on theoretical assumptions from non-COVID diseases such as ARDS, SARS or MERS that have distinct etiology, epidemiology, phenotypes and outcomes. Instead, you can highlight even though CS have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large.

→ We agree with the aforementioned. We have changed it. “Corticosteroids (CS) have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large.”

Methods: Study conclusion: consider renaming this section Study endpoints to avoid confusion with the use of the word conclusion. The Literature search section does not add to the methods, consider removing.

→ We agree with the aforementioned. We have changed it.

There are 2 definitions of megadoses, >150 mg of prednisone in 3-4 days and >150 mg of prednisone in 24h. Historically, high-dose CS in ARDS research has been defined as >200mg/Kg/day of methylprednisolone or its equivalent in other CS forms (prednisone, prednisolone, etc). If the authors choose to study >150mg of prednisone then I would recommend using the definition of >150mg in 24h and report the cumulative dose of steroids AND the daily dose in a "mg/Kg/day" format to keep up to the literature.

→ We agree with the aforementioned. We have changed it. “The definition of >150mg in 24h”. About the cumulative dose of steroids AND the daily dose in a "mg/Kg/day", we cannot use this format, because we do not have data to calculate it.

Results: Overall the results are focused on all patients receiving CS vs those who didn't, and then in CS megadoses vs no megadoses. I believe it would be more useful to change to 3 groups in the tables: No CS, low-dose CS and CS megadoses.

→ We agree with the aforementioned. We have changed it.

Table 2 is too long, try grouping comorbidities to clinically relevant terms that are well known risk factors for COVID, such as chronic lung disease, chronic cardiovascular disease, renal insufficiency, etc. Table 1 can be integrated at the end of table 2 as it does not add much as a stand-alone table. Revise spelling in the tables.

→ We agree with the aforementioned. We have changed it.

For table 4 and 5 it would be more useful merged to have the mean/median of lab values instead of the proportion of abnormal labs in both groups as this can be misleading. Table 7 would be more useful if describing megadoses vs regular steroids. Consider adding APACHE, PaFiO2, or other proxies to clinical status upon admission.

→ We agree with the aforementioned. We have changed it.

There are higher inflammatory markers in patient's receiving megadoses according to tables 4 and 5, this creates an uneven populations to compare the effect of megadoses. There are 2 ways to address this unbalance: inverse weight proportion analysis and propensity-score matching. Consider using one of these to strengthen results.

→ Thank you for your input. We have tried to strengthen the results with multivariate analysis.

Mortality metric used in too broad including follow-up of patients already discharged, with a median hospital stay of 12 days, using 30-day mortality would be preferred.

→ We agree with the aforementioned. We have changed it.

Reviewer #2: From my point of view, it is of little interest to focus the study on the differences between patients who have received megadoses and those who have not. It is much more interesting to find out if the megadoses had negative consequences, in terms of complications, hospital stay or mortality.

Most of the conclusions drawn by the authors are based on bivariate analyzes, which in an observational study like this one, have no more value than merely descriptive. As the authors note, there are a large number of important differences between patients treated with megadoses and those who are not, so the results in terms of complications or mortality are very difficult to interpret. The authors carry out a single multivariate analysis on mortality, in which they have only introduced a few, of the many factors that they have found asymmetrically distributed between groups, without providing an explanation of the selection process carried out. That is, there are enough confounding factors missed in the analysis, so the results most likely have residual confusion. In addition, some important confounding factors that can affect health outcomes in COVID-19 do not seem to have been available, such as saturation and the rest of vital signs, respiratory support, etc. Also, Multivariate analysis, which is essential in this type of observational studies, is limited to mortality results, and has not been done for other interesting results such as, for example, complications of the disease.

Unfortunately, I do not believe that the results are valid for the outcomes of greatest interest, due to the lack of control for relevant confounders, so I cannot recommend the publication in its current state. However, the authors have a valuable database, and their idea of comparing the effect of high doses with other doses of steroids is interesting. I encourage them to choose a relevant outcome, such as mortality, and do a full multivariate analysis, which attempts to elucidate whether mega-doses are associated with higher mortality. They also have an exceedingly large sample, to match patients in whom megadoses were used, with controls with similar clinical characteristics, in which megadoses were not used. In short, they have many possibilities with this database, and I am sure they can make a much more robust analysis than the one presented here, to provide new knowledge about corticosteroids effect in this disease.

→ We agree with the suggested changes. We have performed the multivariate analysis in mortality and have also focused on the possible adverse effects of megadoses therapy.

Thank you for all your comments. We hope to have addressed them in the hope of moving the work forward for early publication.

Kind regards,

Cristina Lavilla

Submitted filename: renamed_42b84.docx

Click here for additional data file.

9 Dec 2021

Use of Glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19.

PONE-D-21-21800R1

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