The efficacy of high-dose pulse-therapy versus low-dose intravenous methylprednisolone on severe to critical COVID-19 clinical outcomes: A randomized clinical trial study

doi:10.21203/rs.3.rs-2202139/v1

Objectives

It remains unclear which formulation of corticosteroid regimen has the optimum efficacies on COVID-19 pneumonia. Herein we evaluated two regimens including methylprednisolone at a dose of 1 mg/kg every 12 hours (low-dose group) and 1000 mg/day pulse-therapy for 3 days following 1 mg/kg every 12 hours (high-dose group) methylprednisolone to assess the clinical outcomes in acute respiratory distress syndrome (ARDS) due to COVID-19.

Methods

This randomized clinical trial was performed on patients with mild to moderate ARDS following COVID-19 randomly assigned to receive low-dose (n = 47) or high-dose (n = 48) intravenous methylprednisolone. Two groups were matched for age, gender, BMI, comorbidities, leukocytes, lymphocytes, neutrophil/lymphocyte, platelet, hemoglobin, and inflammatory markers (ESR, CRP, Ferritin). both regimens were initiated upon admission and continued for 10-days. the clinical outcome and secondary complications were evaluated.

Results and discussion

Evaluating in-hospital outcomes, no difference was revealed in the duration of ICU-stays (5.4 ± 4.6 vs 4.5 ± 4.9, p-value = 0.35), total hospital-stays (8 ± 3.1 vs 6.9 ± 3.4, p-value = 0.1), requirement rate for invasive ventilation (29.2% vs 36.2%, p-value = 0.4) or none-invasive ventilation (16.6% vs 23.4%, p-value = 0.4), and hemoperfusion (16.6% vs 11.3%, p-value = 0.3) between the groups. Fatality due to ARDS (29.2% vs 38.3, p-value = 0.3), and septic shock (4.2%, 6.4%, p-value = 0.3) was respectively reported in low-dose and high-dose groups, with no significant difference. Patients who received pulse-therapy had significantly higher bacterial pneumonia co-infection events (18.7% versus 10.6% (p-value = 0.01).

What is new and conclusion: adjuvant pulse-therapy for intravenous methylprednisolone does not improve the in-hospital clinical outcomes among mild to moderate ARDS COVID-19 patients. Higher risk of Bacterial pneumonia should be considered in such cases receiving the higher dose of steroids.

COVID-19

corticosteroids

methylprednisolone

steroid pulse therapy

Coronavirus disease (COVID-19) infection, as a global health concern, has led to a severe crisis and a massive number of deaths since the pandemic emergence[1, 2]. Whilst the global vaccination has controlled the soaring rate of afflictions and fatalities in the majority of countries, there is still evidence of new waves of disease transmission in some nations. Infection with the virus could result in clinical manifestations with a spectrum of severity from mild to severe, and even leading to sudden death[3, 4]. The elderly with cardiometabolic co-morbid factors is more likely to experience the worse form of infection with poor clinical outcomes[5, 6]. The pathological hyperimmune response following the cytokine storm syndrome due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection could play a decisive part in the patient's clinical outcome[7]. Such individuals could have endothelial lung injury as well as micro- and macro-vascular thromboembolism events, which cause severe lung damage as well as multiple organ failures[8]. Evidence has shown that corticosteroids may possess anti-inflammatory effects that mitigate hyperimmune response in severe COVID-19 cases, hence preventing the risk of respiratory failure[9–11]. The World Health Organization (WHO) firmly advises treating severe COVID-19 infections that require long-term respiratory support with low-dose systemic steroid therapy for a maximum of ten days[12]. Even though different dosages and formulations of steroid therapy have been trialed on COVID-19 patients over the previous two and a half years of the pandemic, data about the efficacy of high-dose corticosteroids as pulse methylprednisolone prior to initial regular steroid therapy is yet to be fully revealed[9, 11, 13]. Herein, we aimed to evaluate and compare the influence of daily 1 mg/kg methylprednisolone versus 1000 mg pulse-therapy of methylprednisolone before the daily 1 mg/kg methylprednisolone on clinical outcomes, including hospital stay duration, the need for intensive care, and in-hospital mortality amongst patients who were diagnosed as mild to moderate ARDS due to SARS-CoV2 pneumonia.

2.A. Study design and participants: This randomized, controlled, parallel-group clinical trial has aimed to investigate the effectiveness of daily methylprednisolone 1mg/kg/ 12 hours regimen versus 3-day pulse methylprednisolone 1000 mg prior to methylprednisolone 1mg/kg/ 12 hours regimen in hospitalized COVID-19 cases with mild to moderate acute respiratory distress syndrome (ARDS) who were hospitalized in a major referral center of COVID-19 patients during the pandemic in Tehran, Iran. Mild to moderate ARDS was defined based on the Berlin Criteria, an American-European Consensus Community (AECC) guideline for staging the severity of ARDS: the PaO2 to FiO2 ratio between 100 to 300 OR 2. The SpO2 to FiO2 ratio of 143 to 343. All enrolled patients were older than 18 years, admitted within the first 24 hours of hospitalization when entered into the study, and did not require invasive mechanical ventilation based on their clinical status. The initial suspicion of SARS-COV2 pneumonia was conducted based on clinical presentations and chest computed tomography, which was confirmed by a real-time polymerase chain reaction (rt-PCR) test for all individuals. Exclusion criteria were pregnancy or active lactation, identified contra-indication to corticosteroid usage, or a history of dexamethasone allergy, daily intake of oral or intravenous corticosteroid in the past 15 days, expected death within the next 72 hours, the need for invasive ventilation upon admission, uncontrolled hypertension (systolic blood pressure more than 150 mmHg at the time of admission), being on chronic hemodialysis, having cardiac failure with Ejection Fraction of < 40% or pulmonary edema, severe vasogenic shock (need for norepinephrine infusion > 300 ng/kg/min), acute or chronic kidney failure, hepatic disease, having a terminal disease and life expectancy of under six months, not starting prednisolone after 24 hours of admission, and refusal to consent to participate in the trial.

2.B. Randomization: Cases were assigned randomly in a 1:1 ratio to receive standard care methylprednisolone 1 mg/kg/day for ten days (low dose group) or pulse of methylprednisolone 1000 mg/day for three days, followed by 1mg/kg/day for an additional ten days (high dose group). A computer software generated the randomization sequence in blocks of six without stratification. The allocated therapy was not concealed from doctors, patients, or those who evaluated the results (non-blinded study). Further, the National Committee of the Iranian Ministry of Health essentially designed all clinical intervention procedures, including those involving the use of antiviral medicines, antibiotics, additional immunomodulators, anticoagulants, and laboratory tests. The pneumology and infectious diseases departments of the hospital bestowed the choice upon the medical team to decide the initial dosage or eliminate therapeutic options due to the drug's side effects in exceptional cases.

2.C. Procedures: A total of 95 cases participated in the study based on the block randomization method, which was divided into two groups. 47 cases were administered with 1 mg/kg methylprednisolone every day for ten days, and the other group included 48 patients who received methylprednisolone at the dose of 1000 mg daily for three days and then the same 1 mg/kg every day for the next ten days. The following data of all patients were collected on Hospital admission: demographics, home treatments, coexistent disorders, the period from Hospital admission to randomization, the period from initial symptoms to randomization, laboratory tests on randomization (lymphocytes, leukocytes, C-reactive protein, D-dimer, Lactate dehydrogenase, procalcitonin, serum ferritin, biochemical parameters, ESR). All patients were monitored all the time by measuring their systolic blood pressure, oxygenic saturation, pulse rate, as well as lead V2 electro-cardio-monitoring. The main aim of this study was to determine the length of hospital stay, rate of invasive ventilation requirement, hemoperfusions, immunological intervention, and mortality in each group and to compare the findings.

2.D. Statistical analysis: Categorial and continuous variables were presented as case number (percentage) and mean ± standard deviation, respectively. All data were analyzed to be confirmed as being normally distributed by the Shapiro-Wilk test. To compare the categorical variables, Fisher's exact or Chi-Squared test was utilized when appropriate. Independent t-test, or Mann–Whitney U test, has been employed for comparison of means between continuous variables as necessitated. Two-sided P values of less than 0.05 were deemed as statistically significant. All the statistics have been conducted utilizing software SPSS version 27.0 for windows (IBM, Armonk, New York, United States).

2.E. Ethical considerations: The proposal for this trial was reviewed and approved on march 16 2021, by the Ethics Committee of Shahid Beheshti university of medical sciences in Iran (ethical code:IR.SBMU. INFECTIOUS.1400.02159, Trial Registration Number: IRCT20130917014693N13, Date: 2021-11-06). The study was carried out in conformity with Good Clinical Practice (GCP) principles, the Declaration of Helsinki, regional regulations, and the national protocol for the care of hospitalized COVID-19 patients. All the patients provided informed consent before randomization. The authors originally established the trial design, gathered the data, and conducted the analytical evaluations. The manuscript's correctness and data integrity were attested to by all authors, who also read and approved it.

We categorized patients into two groups: 48 patients who received the dose of 1 mg/kg per 12 hours methylprednisolone (low dose methylprednisolone group) and 47 patients who received 1000 mg pulse methylprednisolone per day for three days following the dose of 1 mg/kg per 12 hours methylprednisolone (high dose methylprednisolone group) (Fig. 1). Two groups were matched based on the age (54.8 ± 15.0 vs. 60.1 ± 16.4; p-value = 0.1), male gender (58.3% vs. 59.6%; p-value = 0.9), and BMI (28.3 ± 3.6 vs. 28.0 ± 4.2; p-value = 0.2) (Table 1). Further, two groups were statistically similar in terms of the prevalence of cardiometabolic comorbidities including diabetes mellitus (16.6% vs. 19.1%; p-value = 0.7), hypertension (16.6% vs. 17%; p-value = 0.7), dyslipidemia (22.9% vs. 27.6%; p-value = 0.5), hypothyroidism (10.4% vs. 4.2%; p-value = 0.2), and coronary artery disease (14.6% vs. 12.8%; p-value = 0.7) (Table 1). Upon hospital admission, the levels of blood-cell count indices including leukocytes (8.4 vs. 8.6; p-value = 0.365), lymphocytes (1.6 vs. 1.6; p-value = 0.325), neutrophil to lymphocyte ratio (3.62 vs. 3.64; p-value = 0.196), hemoglobin (13.9 vs 13.7; p-value = 0.124) and platelets (169.2 vs. 166.5; p-value = 0.369) did not have a significant difference between the groups (Table 1). Also, the inflammatory biomarkers such as Erythrocyte sedimentation rate (32.4 vs. 33.1; p-value = 0.485), C-reactive protein (16.3 vs. 14.9; p-value = 0.241), and ferritin (365.2 vs. 375.3; p-value = 0.399) showed similar increments in amount, within both study groups (Table 1).During hospitalization, some of the patients in both high-dose and low-dose methylprednisolone groups received Remdesivir, and Tocilizumab; though the number of patients receiving Remdesivir (18.7% vs. 17.0%; p-value = 0.829) and Tocilizumab (27.0% vs. 12.8%; p-value = 0.081), as well as the average received dosage of these medications were similar in both group with no significant difference (5.06 vs. 4.67 mg; p-value = 0.103 for Remdesivir dose, and 0.73 vs. 0.53 mg; p-value = 0.933 for Tocilizumab dose) (Table 2). Moreover, the number of patients who required hemoperfusion (16.6% vs. 11.3%; p-value = 0.395) as well as the sessions of hemoperfusion were similar in groups (0.91 vs. 0.61; p-value = 0.756) (Table 2). No significant difference was found in neither the rate of patients who required invasive ventilation (29.2% vs. 36.2%; p-value = 0.466) nor the duration of intubation amongst those who were under invasive ventilation in both groups (3.77 vs. 2.09 days; p-value = 0.25). Similarly, patients receiving high-dose methylprednisolone had close rates of being under non-invasive ventilation compared to the low-dose methylprednisolone group (16.6% vs. 23.4%; p-value = 0.409). Of note, the number of patients transferred to ICUs (70.8% vs. 57.4%; p-value = 0.124), the length of ICU stays (5.44 vs. 4.52 days; p-value = 0.356), and the total duration of hospital stay (8 vs. 6.91 days; p-value = 0.114) were all statistically similar in both study groups. After being eligibly discharged, patients of the two groups had similar oxygenic saturation (87.19 ± 3.83% vs. 86.64 ± 3.83%, p-value = 0.5) (Table 2). Bacterial pneumonia and septic shock, as in-hospital complications, were evaluated in patients. Whilst the rate of septic shock did not have a remarkable difference between the groups (4.2% vs. 6.4%; p-value = 0.629), patients who were under 72-hour 1000 mg pulse of methylprednisolone before regular dosage therapy were reported to develop considerably more bacterial pneumonia co-infection (18.7% vs. 10.6%, p-value = 0.01). However, one must notice that eventually, the rate of fatality did not differ between the two groups (29.2% vs. 38.3%; p-value = 0.346) (Table.3).

The results of this research showed that patients with mild to moderate ARDS receiving 1000 mg/day pulse therapy of methylprednisolone before starting 1 mg/kg/12 hours methylprednisolone did not experience any increased survival, decreased ICU stay and overall hospital stay, or improved rates of mechanical ventilation or NIV. But the risk of bacterial pneumonia co-infection was considerably greater in the group receiving large doses of methylprednisolone.

The two effective evidence-based treatments that are now in widespread use for hospitalized patients with COVID-19 are systematic corticosteroids and Remdesivir[9, 11, 14]. In fact, amongst immune modulating agents, steroids have been found to slow the development to respiratory failure and mortality in cases of severe COVID-19 pneumonia with cytokine storm syndrome[7, 9].

By preventing macrophages from performing their phagocytic roles and by lowering the activities along with the quantity of T cells while having little to no effect on humoral immunity, glucocorticoids possess their suppressive effects on human immune system[15]. Rapid Evidence Appraisal for COVID-19 Therapies (REACT), the WHO’s biggest meta-analysis of clinical studies, has shown that systemic steroid therapy among severe COVID-19 patients is helpful in lowering in-hospital mortality[12, 16].

The WHO has issued recommendations for the use of low-dose steroid therapy in the treatment of severely sick COVID-19 patients, emphasizing their advantages in reducing mortality and the requirement for mechanical ventilation; while also advising against the use of it in mild to moderate cases[16]. Other studies have shown that early steroid treatment could lower mortality, decrease the number of days that ARDS patients require invasive ventilation, and increase the number of days when organ support is not required[9–12, 15, 17, 18] .These findings demonstrate once more how systemic steroid therapy might increase the likelihood of survival.

Nevertheless, up until recently, there is no strong consensus agreement on the standards for the amount of steroid administration for COVID-19 patients and most of the data showing the advantages of corticosteroids in COVID-19 came from observational researches rather than clinical trial studies[19, 20]. consistent with our findings previous retrospective observational studies showed that glucocorticoid pulse treatment did not appear to be more advantageous than lowering dosages in COVID-19.[21]. Moreover, research by Steinberg K et al. [22] on COVID-19 patients with ARDS taking Methylprednisolone found a high death rate of around 30% compared to low-dose receiving patients with fatality rate of 18%. Other studies found that individuals with comorbid conditions and older age were being at higher risk of death while taking high doses of methylprednisolone[23, 24].

On the other hand, some research has supported the use of methylprednisolone in critically ill patients with severe COVID-19 [26]. In instances of severe SARS-CoV-2 pneumonia treated with 1 to 2 mg/kg/day of methylprednisolone over the course of 7 days, Youx et al. [25] principally observed a quicker improvement of oxygen saturation and a shorter duration of fever. further, high-dose Methylprednisolone was found to be superior to Dexamethasone in studies by Pinzon M et al.[26] and Ranjbar K,[27] in improving clinical condition and decreasing the need for invasive ventilation. The fact that methylprednisolone could reach into the lungs more extensively rather than dexamethasone may be the cause of this advantageous impact, which would make it more effective in improving lung compliance. Although, in the aforementioned investigations, the mortality rate improvement was not statistically significant. Similar to this, several investigations have shown that early methylprednisolone therapy could improve clinical outcomes in hypoxic individuals with more severe illness[28].

Notably, amongst types of corticosteroids, we preferred to administer methylprednisolone for COVID-19 patients who were qualified. Methylprednisolone is a readily accessible, inexpensive corticosteroid that has been utilized more frequently than other corticosteroids in ARDS studies. Methylprednisolone, an intermediate-acting medication, has a 5-fold potency advantage over short-acting medications such as hydrocortisone. while Dexamethasone, a long-acting medication, has a 25-fold advantage over short-acting medications and has been used in several settings due to COVID-19 pandemic[26, 29]. Additionally, because methylprednisolone has little to no mineralocorticoid action, it won't increase the risk of fluid retention (a sodium/water mismatch), which is typically found in severe ARDS cases[30].

We discovered that individuals receiving large doses of steroids had a greater risk of concurrent bacterial pneumonia. Observational data currently available point to a greater risk of subsequent fungal or bacterial infections after corticosteroid usage in viral syndromes, as was previously seen in influenza[31], and a compromised immune response in respiratory syncytial virus (RSV)[8, 32]. In our investigation, methylprednisolone-using individuals did not have a greater incidence of septic shock. All patients were hospitalized and taking a macrolide and Ceftriaxone at the same time, which may have complicated the accurate assessment on this possible adverse effect of corticosteroid treatment. It is worthy to be noted that amongst the septic shock, corticosteroid medications have been employed to raise systemic vascular resistance and boost mineralocorticoid function in an effort to restore effective blood volume[33, 34].

Regarding the absolute efficacy of corticosteroids in COVID-19, numerous issues remain unresolved. Notably, a recent systematic analysis of corticosteroid trials revealed that MERS-CoV-1 and SARS-CoV-1 had delayed viral clearance. Because of the possibility of increasing viral shedding after the steroid is suppressed, if such medications are taken in early illness, they should likely be continued for more than five days or until clinical improvement is apparent. Although we did not have the opportunity to assess this consequence in our investigation, high-dose corticoids have been demonstrated to affect long-term viral shedding35. This theory has to be validated, and longer virologic follow-up is required in future studies.

This study had some strengths, including that it was performed in a public hospital setting; in compatible with appropriate clinical practices, and designated to assess the role of adjuvant steroid pulse-therapy which is rarely assessed in previous literature[13]. It also had several limitations which are as follows: 1. low sample size of the study which limited us better evaluating minor differences between the case and control groups; 2. a single-center setting; 3. relatively high fatality rate (overall 33.7%) as compared to other similar studies reports which could be almost explained by subject’s demographic and increased prevalence of co-morbidities; 4. And last but not least ,the lack of data to estimate the role of these regimens on leading complication of COIVD-19 such as pulmonary fibrosis.

we found that use of methylprednisolone pulse-therapy during the first 3 days of hospitalization before 1 mg/kg/12 hours methylprednisolone was not sufficient to improve the prognosis, in hospital events and final outcome. Our analysis also showed that pulse-therapy with methylprednisolone increases bacterial co-infection pneumonia in hospitalized patients with COVID-19. Further studies are required to disclose whether clinicians should increase the dosage of steroids in the battle against COVID-19 or take the cautions regarding the increasing chance of bacterial pneumonia. Further, more evaluations the prolonged adverse effects, which are frequently dose-dependent, could help clinicians to decide between regimens if both of the dosing formulations are verified to have the equivalent efficacies in clinical outcomes.

Ethics approval and consent to participate: The proposal for this trial was reviewed and approved on March 16 2021, by the Ethics Committee of Shahid Beheshti university of medical sciences in Iran (ethical code: IR.SBMU.INFECTIOUS.1400.02159.) (Trial Registration Number: IRCT20130917014693N13, Date: 2021-11-06)

Consent for publication: All the patients provided informed consent before randomization, trial and before drafting and submission.

Availability of data and materials: The data used during the current study available from the corresponding author on reasonable request.

Competing interests: no conflict of interest is declared by the authors.

Funding: None

Authors' contributions: PP, ZS, MA, IAD conducted the trial. ZS, IAD, PP conceptualized the trial. SA, FET, IAD prepared the manuscript. JS criticized the manuscript.

Acknowledgments: The authors would like to thank the Clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their help and support in conducting this study.

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Table.1: Baseline characteristics of the patients with COVID-19 pneumonia.
p-value	Low dose methylprednisolone	High dose methylprednisolone	Characteristic
-	47	48	Number
Sociodemographic
0.103	60.17±16.49	54.83± 15.05	Age, year
0.933	28(59.6)	29(58.3)	Gender, male
0.239	28.0±4.2	28.3±3.6	Body mass index, kg/m2
Comorbidity
0.756	9 (19.1)	8 (16.6)	Diabetes mellitus
0.751	8 (17.0)	8 (16.6)	Hypertension
0.599	13 (27.6)	11 (22.9)	Dyslipidemia
0.799	6 (12.8)	7(14.6)	Coronary artery disease
0.250	2 (4.2)	5 (10.4)	Hypothyroidism
Laboratorial
0.365	8.6±2.5	8.4±2.2	Leukocytes, cells/ml
0.325	1.6±0.5	1.6±0.76	Lymphocytes, cells/ml
0.196	3.64±1.2	3.62±1.0	Neutrophil /lymphocyte, ratio
0.124	13.7±1.2	13.9±1.5	Hemoglobin g/dl
0.369	166.5±6.2	169.2±5.7	Platelet, cells/ml
0.485	33.1±4.6	32.4±5.3	Erythrocyte sedimentation rate, mm/hr.
0.241	14.9±3.6	16.3±5.3	C-reactive protein, mg/l
0.399	375.3±99.2	365.2±72.1	Ferritin, ng/ml

Table.2: Therapeutics and interventions received during admission due to COVID-19 pneumonia.
p-value	Low dose methylprednisolone	High dose methylprednisolone	Therapeutic
-	47	48	Number
0.829	8 (17.0)	9 (18.7)	Received Remdesivir
0.103	4.67±0.935	5.06±1.17	Remdesivir dose, mg
0.081	6 (12.8)	13 (27.0)	Received tocilizumab
0.933	0.53±0.19	0.73±0.4	Tocilizumab dose, mg
0.395	5 (11.3)	8 (16.6)	Received hemoperfusion
0.756	0.61±0.19	0.91±0.35	Hemoperfusion sessions
0.466	17 (36.2)	14 (29.2)	Requirement for invasive ventilation
0.250	2.09±1.05	3.77±1.91	Invasive ventilation, days
0.409	11 (23.4)	8 (16.6)	Requirement none-invasive ventilation
0.412	1.1±0.47	1.47±0.25	None-invasive Ventilation, days
0.124	27 (57.4)	34 (70.8)	Requirement for ICU admission
0.356	4.52±4.92	5.44±4.65	ICU stay, days
0.114	6.91±3.42	8±3.19	Hospital stays, days
0.285	5.17(3.49)	5.90(3.07)	Oxygen support with mask, days
0.593	86.64±3.83	87.19±3.83	Oxygen saturation upon discharge

Table.3: Secondary events during hospitalization due to COVID-19 pneumonia.
p-value	Low dose methylprednisolone	High dose methylprednisolone	Events
-	47	48	Number
0.629	3 (6.4)	2 (4.2)	Septic shock
0.018	5 (10.6)	9 (18.7)	Bacterial pneumonia
0.346	18 (38.3)	14 (29.2)	Mortality

No competing interests reported.

The efficacy of high-dose pulse-therapy versus low-dose intravenous methylprednisolone on severe to critical COVID-19 clinical outcomes: A randomized clinical trial study

Status:

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Abstract

Objectives

Methods

Results and discussion

Figures

1. Introduction

2. Material And Methods

3. Results

4. Discussion

5. Strengths and limitations

6. Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1