Pulse versus nonpulse steroid regimens in patients with coronavirus disease 2019: A systematic review and meta‐analysis

Abstract Systemic steroids are associated with reduced mortality in hypoxic patients with coronavirus disease 2019 (COVID‐19). However, there is no consensus on the doses of steroid therapy in these patients. Several studies showed that pulse dose steroids (PDS) could reduce the progression of COVID‐19 pneumonia. However, data regarding the role of PDS in COVID‐19 is still unclear. Therefore, we performed this meta‐analysis to evaluate the role of PDS in COVID‐19 patients compared to nonpulse steroids (NPDS). Comprehensive literature search of PubMed, Embase, Cochrane Library, and Web of Science databases from inception through February 10, 2022 was performed for all published studies comparing PDS to NPDS therapy to manage hypoxic patients with COVID‐19. Primary outcome was mortality. Secondary outcomes were the need for endotracheal intubation, hospital length of stay (LOS), and adverse events in the form of superimposed infections. A total of 10 observational studies involving 3065 patients (1289 patients received PDS and 1776 received NPDS) were included. The mortality rate was similar between PDS and NPDS groups (risk ratio [RR]: 1.23, 95% confidence interval [CI]: 0.92–1.65, p = 0.16). There were no differences in the need for endotracheal intubation (RR: 0.71, 95%: CI 0.37–1.137, p = 0.31), LOS (mean difference: 1.93 days; 95% CI: −1.46–5.33; p = 0.26), or adverse events (RR: 0.93, 95% CI: 0.56–1.57, p = 0.80) between the two groups. Compared to NPDS, PDS was associated with similar mortality rates, need for endotracheal intubation, LOS, and adverse events. Given the observational nature of the included studies, randomized controlled trials are warranted to validate our findings.


| INTRODUCTION
Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, first discovered in China in December 2019, and has become a worldwide pandemic leading to significant morbidity and mortality. 1,2 The acute respiratory distress syndrome (ARDS) due to viral pneumonitis is one of the leading causes of mortality among patients with COVID- 19. 3 ARDS occurs in 33% of hospitalized patients with COVID-19 and 75% of those who required ICU admission. 4 The average mortality rate among COVID-19 patients with ARDS is 39% (ranging from 13% to 73%). 3 In the absence of specific antiviral therapy for COVID-19, research on the effectiveness of various re-purposed drugs in COVID-19 has become an urgent task of scientists and physicians.
Exaggerated inflammatory response with cytokine storm is the hallmark of moderate to severe cases of COVID-19. 5 In July 2020, the RECOVERY trial showed that low-dose dexamethasone reduced mortality in patients with COVID-19 who need oxygen supplementation. 6 Since then, many studies have been conducted and demonstrated that systemic steroids were associated with reduced mortality in hypoxic patients with COVID-19. 7,8 Systemic steroids work by decreasing the expression of pro-inflammatory cytokines, thus reducing the IL-6 mediated cytokine storm, which prevents further progression of ARDS. 8 However, the role of pulse dose steroids (PDS) in ARDS patients is not well established. PDS entails the use of glucocorticoids, usually methylprednisolone (MTP), delivered at very high doses of 10-20 mg/kg or >250 mg/day and as high as 1 g/day. 9 The use of PDS has been was studied during the SARS and MERS epidemics, with the results being controversial. 10,11 The theory behind using PDS steroids is that the high dose of steroids can counter the hyperinflammatory phase COVID-19 and can help to reduce mortality. 12,13 Although systemic steroids have shown a mortality benefit in COVID-19, there is no consensus on the doses of steroids therapy in these patients. Newer studies showed that PDS could reduce the progression of COVID-19. [14][15][16] Several studies have compared PDS versus nonpulse dose steroids (NPDS) with conflicting results. 14,[17][18][19] Data regarding the role of PDS in COVID-19 are still unclear.
Therefore, we performed this meta-analysis to evaluate the effect of PDS versus NPDS on the clinical outcomes of patients with COVID-19 pneumonia.

| Data sources and search strategy
We performed a comprehensive search for published studies indexed in PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science from inception to February 10, 2022. We also performed a manual search for additional relevant studies using references of the included articles. The following search terms were used: ("pulse dose" or "high dose"), ("methylprednisolone" or "dexamethasone" or "hydrocortisone" or "prednisone" or "glucocorticoids" or "steroids"), and ("COVID" or "COVID-19"). The search was not limited by language, study design, or country of origin.
Supporting Information: Table S1 describes the full search terms used in each database searched.

| Inclusion and exclusion criteria
All peer-reviewed studies that compared PDS versus NPDS in COVID-19 patients and reported one of the following outcomes: mortality, need for endotracheal intubation, length of stay (LOS), or adverse events were eligible for inclusion. PDS therapy should be clearly defined and must meet the following criteria: a dose of >250 mg of methylprednisolone (MTP) or 5-10 mg/kg/day of MTP or an equivalent dose of glucocorticoids (GC) must be administered to >75% of the PDS group for at least two consecutive days. NPDS cohort should receive any dose less than the PDS doses. We excluded single-arm studies, case reports, case series, reviews, editorials, abstracts, and preprint studies.

| Data extraction
The following data were extracted from the studies: first author name, publication year, country of origin, study design, sample size, gender of patients, mean age, and underlying comorbidities of the patients, including asthma and other chronic lung diseases, malignancy, coronary artery disease, and chronic kidney disease or acute kidney injury. We also obtained inclusion criteria in each study and respiratory support used in each study. For each arm of the study, the detailed PDS and NPDS treatment regimens were extracted.
Outcomes measures were also retrieved, including mortality, need for endotracheal intubation, LOS, and superimposed infection.

| Outcomes
The primary outcome of our study was mortality. The secondary outcomes were the need for endotracheal intubation, LOS, and adverse events in the form of superimposed infections or bacterial growth in cultured bodily fluids.

| Statistical analysis
We performed a meta-analysis of the included studies using Review A p < 0.05 was considered statistically significant. The heterogeneity of the effect size estimates across the studies was quantified using the Q statistic and I 2 (p < 0.10 was considered significant). A value of I 2 of 0%-25% indicates significant homogeneity, 26%-50% low homogeneity, and >50% indicates heterogeneity. 20

| Sensitivity and subgroup analyses
To confirm the robustness of the results, sensitivity analysis for all outcomes (mortality, need for endotracheal intubation, LOS, and adverse events) using a leave-one-out meta-analysis was performed to see if it had a significant influence on the result of the metaanalysis. Subgroup analysis was performed for studies that only included patients who received dexamethasone (DEXA) only in the NPDS group and based on the PDS therapy strategy (initial vs. rescue therapy) for mortality.

| Bias assessment
We assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS) for observational studies. 21 Two authors (W. K. and A. B.) independently assessed each study for bias. Discrepancies were resolved by a third reviewer (O. S.). Publication bias was assessed for mortality qualitatively by visualizing the funnel plot and quantitively using Egger's regression analysis. A p-value was generated using the Egger analysis, and a value of <0.05 was associated with significant publication bias.

| Study selection
A total of 10,130 studies were retrieved by our search strategy.
Seven thousand two hundred fifty-three studies were excluded based on the title and abstract review. A total of 1568 studies underwent full-length review. Subsequently, we excluded 1558 studies because of the following: 1391 studies used inappropriate doses of steroids or lacked the appropriate comparison, 128 studies did not report data regarding the interventions of interest, and 39 studies were excluded due to lack of the appropriate outcomes of interest. Eventually, 10 studies met our inclusion criteria and were included in the meta-analysis. [14][15][16][17][18][19][22][23][24][25] Figure 1 shows the preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart that illustrates how the final studies were selected. Table 1 shows the baseline characteristics of the studies included in the meta-analysis. All the studies were published between August 2020 and December 2021 and included COVID-19 patients confirmed by laboratory testing or imaging. Based on country of origin: five studies originated from Europe (Italy: 1; Spain: 2; and Turkey: 2), one from Morocco, one from Colombia, one from Japan, one from Pakistan, and one from the United States. Nine studies were retrospective cohort, while one was an ambispective cohort.

| Study and patient characteristics
A total of 3065 patients (1289 patients received PDS and 1776 received NPDS) were included, with males representing 61.8% of the total patients. The mean age of the patients in the PDS group was 56.1 years, and 65 years in the NPDS group. The follow-up period across the studies ranged from 14 to 46 days. Table 2 Figure 3A). Subgroup analysis also showed no significant difference if PDS was given as initial therapy or rescue therapy ( Figure 3B). A leave-one-out sensitivity analysis showed consistent results (Supporting Information: Figure S1A).

| Length of hospital stay
Three studies 17,19,23 reported the LOS. There was no significant difference in the LOS between the two groups (MD: 1.93 days; 95% CI: −1.46-5.33; p = 0.26, I 2 = 91%, Figure 2C). The results were consistent on the leave-one-out sensitivity analysis (Supporting Information: Figure S1C).  Figure 2D). However, on a leave-one-out sensitivity analysis, removal of Umbrello et al. 23 moved the overall effect to favor PDS with an RR of 0.74 (95% CI: 0.56-0.99, p = 0.05, I 2 = 41%), suggesting that Umbrello et al. was partly the reason for the significant between-study heterogeneity (Supporting Information: Figure S1D).  Table S2. All the included studies [14][15][16][17][18][19][22][23][24][25] were of high quality. There was a visible asymmetry in the funnel plot of the studies that reported mortality, which may suggest the presence of publication bias (Supporting Information: Figure S2). However, Egger's regression analysis did not demonstrate statistically significant publication bias (p = 0.86).

| DISCUSSION
This is the first meta-analysis comparing PDS and NPDS regimens in patients with COVID-19 and showed no significant differences between PDS and NPDS regimens in terms of mortality, need for endotracheal intubation, LOS, and adverse events.
Since the RECOVERY trial showed a mortality benefit with steroid therapy due to its anti-inflammatory and immunomodulatory effects, 6   T A B L E 2 Primary and secondary outcomes of the included studies.

Study (year)
In-hospital mortality  There are several adverse events to using steroids, such as superimposed infections/bacterial overgrowth, hyperglycemia, and myopathy. In contrary to Umbrello et al., 23 which showed an increased risk of infections with PDS regimen in addition to mortality, our metaanalysis showed similar rates of infection between the two regimens.
The increased rates of infections within the PDS group in that study could be attributed to the fact that PDS was used as a rescue therapy after lack of response to NPDS regimen, indicating that the PDS group patients were sicker and had more severe features of COVID-19. 23 In addition, PDS group had higher levels of C-reactive protein, IL-6, and D-dimer and a lower Partial pressure of arterial oxygen (PaO 2 ). 23 Interestingly, we found that the infection rate was significantly lower in the PDS group upon removal of that study. This might be explained by the short duration of the PDS regimen.  Assaly supervised and critically revised the manuscript. All authors had access to the data and a role in writing the manuscript. All authors read and approved the final manuscript.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
All data were available to all authors of the manuscript.

ETHICS STATEMENT
This study was deemed exempt by the Institutional Review Board of the University of Toledo, as it was a meta-analysis of published studies that included deidentified patient information.