Highlights•

Dexamethasone was more effective than methylprednisolone for covid-19.

•

Hospitalization time was shorter in the dexamethasone group.

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Duration of oxygen therapy was shorter in the dexamethasone group.

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Hypokalemia and hyperglycemia were higher in the methylprednisolone group.

AbstractObjective

To compare the effects of intravenous dexamethasone and methylprednisolone on the treatment of inpatients with COVID-19.

Methods

In this randomized clinical trial, 143 patients under 80 years of age with moderate to severe COVID-19 were enrolled and randomly assigned to two groups: dexamethasone (8 mg/day) and methylprednisolone (60 mg/day in two divided doses). The primary outcome was the length of hospital stay and the secondary outcomes included: duration of oxygen therapy, absolute leukocyte and lymphocyte count, hypokalemia, hyperglycemia, ICU admission, and mortality in the two groups for 28 days. Data were analyzed by SPSS 26 using t-test, chi-square and ANOVA.

Results

The duration of hospitalization was significantly (p<0.001) shorter in the dexamethasone group in compared with methylprednisolone group [8 (95% CI:6-10) and 11 (95% CI:7-14), respectively]. In addition, duration of oxygen therapy in the dexamethasone group [7 (95% CI:5-9)] was significantly (p<0.001) shorter in compared with methylprednisolone group [10 (95% CI:5.5-14)]. The mortality rate was 17.1% (95% CI: 8.1-26.1) in dexamethasone group and 12.3% (95% CI: 4.6-20.0) in methylprednisolone group which was not statistically significantly (P=0.46).

Conclusion

Results showed better effectiveness of 8 mg/day dexamethasone compared to 60 mg/day methylprednisolone based on the shorter hospital stay, which can be taken into consideration in the therapeutic protocol of COVID-19.

Trial registration: IRCT20210223050466N1

Keywords

Introduction

Coronavirus disease 2019 (COVID-19), caused by coronavirus, is the cause of a global pandemic that began in Wuhan, China in December 2019. The disease progresses in approximately 19% of the patients and leads to severe pneumonia, and in 5% of patients, critical pneumonia (Wu and McGoogan, 2020).

Acute Respiratory Distress Syndrome (ARDS) may begin during the second week, not only because of the excessive replication of the virus but also because of the severe inflammatory response. The mechanism of viral entry to the human host cell is fulfilled by a cellular surface protein called angiotensin-converting enzyme 2 (ACE2) and priming of the viral spike protein by the transmembrane protease serine 2 (TMPSS2). The fusion of the virus to host cell occurs through cleavage step and finally cell entry (Matarese et al., 2020). The corona viruses express and replicate their genomic RNA that are incorporated into new viral particles (V`kovski et al., 2021). After uncontrolled replication of the virus, which increases the number of infected epithelial cells and cellular debris, large amounts of cytokines are released accompanied by severe inflammation, which reduces CD4+ memory T helper cells and increases the cytotoxic activity of CD8 (Guan et al., 2020, Shi et al., 2020).

In the early stages of the disease, the antiviral immune response leads to the elimination of the virus but the inflammatory response leads to lung damage. Lung damage begins at the epithelial-interstitial-endothelial level, and exudates from neutrophils and macrophages reduce the surfactant, leading to decreased alveoli ability and oxygen exchange. The debris of infected cells releases inflammatory cytokines such as TNF-α and interleukins 1 and 6, referred to as cytokine storm (Sweeney and McAuley, 2016).

In the second phase, excessive replication of the virus leads to cytotoxicity due to the ACE2 followed by activation of the immune cycle and exacerbation of the inflammatory condition. In this phase, the patient develops lymphopenia with a decrease in CD4, CD8, T and NK cells. Cytokine storm leads to widespread vascular inflammation, massive coagulation, shock, hypotension, and ultimately organ failure and death. Studies have shown that any factor that prevents these events can prevent lung damage and pulmonary thromboembolism (Wang et al., 2020). Given this physiopathology, it seems that corticosteroid intervention may be effective.

Corticosteroids, however, suppress the immune system and therefore raise fears about the spread of the virus. Severe or critical pneumonia is expected not to increase with a relatively short maintenance dose (Isidori et al., 2020). In one study, in hypoxic inpatients, methylprednisolone yielded better outcomes in terms of hospital stay length and clinical conditions (Ranjbar et al., 2021). However, two studies published in the Lancet have recommended the use of corticosteroids for the treatment of COVID-19, but these studies have been based mainly on similar viruses than on COVID-19 alone (Russell et al., 2020, Shang et al., 2020). Besides this, the WHO and the Center for Disease Control and Prevention (CDC) have recommended that corticosteroids not be used to modulate immunity (CDC, 2020, Organization, 2020). However, other guidelines on sepsis in COVID-19 recommend the use of corticosteroids in intubated patients with ARDS to reduce inflammatory response and treat secondary adrenal insufficiency in sepsis, especially in patients with refractory shock. However, the same guidelines in other reports have advised not to use corticosteroids in intubated patients without ARDS (Alhazzani et al., 2020). In an animal study, methylprednisolone led to a higher ratio of lung tissue-to-plasma than dexamethasone, showing that it could be more effective for lung damage (Annane et al., 2017). In a human study, treatment outcomes were significantly better in severe COVID-19 patients who needed oxygen or mechanical ventilation and underwent treatment with dexamethasone (Horby et al., 2020). Dexamethasone has been reported to have no mineralocorticoid effect and to produce the highest anti-inflammatory effect and half-life among corticosteroids (Samuel et al., 2017).

Patients' medical history also affects the prognosis of the disease. The increased ACE2 glycation and TMPSS2 expression in cardiomyocytes in patients with diabetes mellitus (DM) versus patients without DM may favor COVID-19 entry that leads to clinical outcomes worsening and cardiovascular events in COVID-19 patients with DM (D`Onofrio et al., 2021). The prognosis of patients with COVID-19 with elevated blood glucose may worsen due to increased risk of severity of disease, mortality, mechanical ventilation, shock and ICU admission because of multiple organ failure (Sardu et al., 2020a, Sardu et al 2020b). Moreover, there is higher binding affinity between ACE2 and COVID-19 in patients with hypertension that leads to higher rate of infection and worsens the prognosis (Sardu et al., 2020b).

Therefore, given the inconsistency in available evidence on the effects of glucocorticoids, this study aimed to comparatively investigate the effects of dexamethasone and methylprednisolone on COVID-19 inpatients' symptoms, hospital stay length, need for ICU admission, mortality and inflammatory markers.

Method

This randomized clinical was conducted between April 2021 and June 2021 in Hajar Hospital of Shahr-e-Kord province, Iran. A total of 143 COVID-19 patients were enrolled and followed up for 28 days (Figure 1).

Figure 1Flow diagram of the study.

Study population

All COVID-19 patients who tested positive by reverse transcription polymerase chain reaction (RT-PCR) test, collected with swab from nasopharynx or other respiratory tract specimens, were examined. Inclusion criteria were age under 80 years, positive RT-PCR test, bilateral lung involvement in high-resolution computed tomography, SpO2<93% and the need for supplemental oxygen, and providing consent to participate in the study. The need for oxygen in patients is fulfilled by (invasive or non-invasive) ventilation or oxygenation by means of cannula or mask.

Exclusion criteria included discharge from hospital before recovery, death within the first 24 hours, acute myocardial ischemia during hospital stay, contraindications to corticosteroids due to underlying disease such as acute hepatitis or fungal infection, and lack of volunteering to participate in the study.

Study outcomes

Duration of hospitalization was considered as the primary outcomes. Secondary outcomes included absolute leukocyte and lymphocyte counts at baseline and completion of hospitalization, hypokalemia, hyperglycemia, the need for ICU admission, duration of oxygen therapy and mortality within 28 days of hospitalization.

Treatment groups

First, the written consent form was completed by the patients and then their demographic information including age, gender, medical history (DM, hypertension, ischemic heart disease, lung disease, kidney disease, autoimmune diseases and hepatitis) was collected. All patients with estimated glomerular filtration rate (eGFR) >30 ml/min and liver enzyme less than five times the upper limit of normal range received remdesivir. All the patients received proton pump inhibitor or H2-blocker to prevent stress ulcer. Those with platelet count >50,000 and fibrinogen >50 mg/dl without active bleeding, if not previously treated with anticoagulant, were treated with prophylactic anticoagulant and those with history of therapeutic dose of anticoagulant or any proven thrombosis while hospitalized received anticoagulants at therapeutic doses. Hyperglycemia was treated with insulin by targeting blood glucose level between 140 and 200 with divided insulin or according to the scale.

The patients were randomly divided into two groups by blocked randomization, and the sample size of each block was decided to be six. Randomization list was prepared using random allocation software. Implementation of the sequence performed by a person who didn't aware from study design and content of the interventions.

One group received intravenous dexamethasone 8 mg/day and the other group received intravenous methylprednisolone 60 mg/day in two divided doses (two thirds of the dose in the morning and one third in the afternoon). Due to the suppression of the immune system by corticosteroids, which increases the likelihood of other infections, patients were treated with corticosteroids for a maximum of 10 days. At baseline, the percentage of arterial blood oxygen was recorded using pulse oximeter for patients needing oxygenation. The patients were followed up during hospital stay and after discharge for 28 days, and the number of days they needed to receive supplemental oxygen was recorded in the two groups. Then, absolute leukocyte and lymphocyte counts at baseline and completion of hospitalization were determined by complete blood count test, and hypokalemia (potassium<3.5 mmol/L) during hospital stay, fasting blood sugar above 126 mg/dL during hospitalization (in duplicate and based on blood sample test), average length of hospital stay, the need for ICU admission, mortality within 28 days of hospital stay (if the patient was discharged before 28 days, he/she was followed up by telephone) and number of days since the onset of symptoms during admission (After statistical analysis, information related to this item was excluded from the study), were recorded in the two groups. Criteria for ICU admission were non-invasive refractory hypoxemia, unstable hemodynamic, decreased level of consciousness, hypercapnia and respiratory distress.

Data Analysis

Data were entered into SPSS version 26 and the mean (±standard deviation) or median (IQR), frequency and percentage were used to describe the data. Data analysis was performed using t-test, Mann-Whitney Test or chi-square.

Results

All patients completed the assigned treatments (Figure 1). The mean age of the methylprednisolone group was 61.74±16.86 years and that of the dexamethasone group 64.51±16.86 years, with no significant difference (P>0.05).The studied groups were not significantly different in terms of gender and underlying diseases including DM, hypertension, ischemic heart disease, lung disease, kidney disease, autoimmune disease and hepatitis (Table 1, P>0.05).

Table 1Comparison of frequency distribution of gender and underlying diseases at admission time in studied groups.

Besides that, the two groups were matched for the levels of SpO2, WBC and lymphocyte count at admission (P> 0.05, Table 2).

Table 2Comparison of mean age, SpO2 and WBC and lymphocyte count at admission time in studied groups.

After the intervention, the comparison of hospital stay length as the main outcome and secondary outcomes such as duration of oxygen therapy, WBC and lymphocyte count at discharge in the studied groups are shown in Table 3. WBC and lymphocyte count at discharge in the two groups were not significantly different (P>0.05), but hospital stay length and oxygen therapy duration were significantly different (PPTable 4).

Table 3Comparison of mean hospital stay length, oxygen therapy duration, WBC and lymphocyte count at discharge time in studied groups.

Table 4Comparison of the frequency distribution of mortality, ICU admission, hypokalemia and hyperglycemia at discharge time in studied groups.

The patients’ medications in the two groups were not significantly different (P>0.05) except for insulin (PTable 5).

Table 5The medications used during hospitalization of patients in studied groups.

No cardiac complication was observed in patients.

Discussion

In the present study, aimed to compare the effects of intravenous dexamethasone and methylprednisolone on the treatment of COVID-19 inpatients, two groups of patients with moderate to severe COVID-19 were treated with dexamethasone and methylprednisolone separately. The results of the present study indicated that dexamethasone was more effective in improving the complications of COVID-19 with a lower risk of hypokalemia and hyperglycemia.

There was no significant difference in mean age and gender between the two groups. In addition, there was no significant difference in medications during hospitalization (except for insulin) and the frequency of underlying diseases [DM (27.4% and 24.3%, respectively), hypertension (50.7% and 44.3%, respectively), ischemic heart disease (11% and 12.9%, respectively), lung disease (15.1% and 10%, respectively), kidney disease (2.7% and 10%, respectively), autoimmune disease (5.5% and 1.4%, respectively) and hepatitis] between the two groups. The SpO2 and WBC and lymphocyte count at admission were not significantly different between the two groups. As well, the need for ICU admission, mortality and ventilation in the two groups were not significantly different. Given that these are considered as risk factors for complications in COVID-19 patients, the studied groups should be homogeneous in this regard (Gattinoni et al., 2020), which was taken into account in the present study. In a study by Fatima et al. (2020) in Pakistan, 100 patients with moderate to severe COVID-19 were treated with either dexamethasone (n=35) or methylprednisolone (n=65) for five days. The two groups were matched for age, smoking, hypertension, lung disease, ischemic heart disease and chronic kidney disease, but were not matched for DM, with the frequency of DM being higher in the dexamethasone group than in the methylprednisolone group (Fatima et al., 2020). One of the limitations of the study of Fatima et al. was small sample size in the dexamethasone group (due to limited access to the drug) and the inequality of the number of diabetic people in the two studied groups. In the present study, similar to the above-cited study, there was no significant difference in mortality (12.3% and 17.1%, respectively) and ICU admission (27.4% and 17.1%, respectively) between the two groups; however, hospital stay length and oxygen therapy duration were significantly shorter in the dexamethasone group. In addition, the side effects of treatments were significantly fewer in the dexamethasone-treated group.

The results of the present study also showed that the two groups were not significantly different in mortality, ICU admission, WBC and lymphocyte count at discharge, but hospital stay length and duration of oxygen therapy were significantly lower in the dexamethasone group than in the methylprednisolone group. In a retrospective, quasi-experimental study conducted by Rana et al. (2020), the medical files of 60 patients with COVID-19 divided into two groups of 30 each, receiving dexamethasone (8 mg twice daily) or methylprednisolone (40 mg twice daily) for 8 days, were studied. It was observed that dexamethasone was more effective than methylprednisolone in reducing C-reactive protein and increasing the PaO2/FiO2 ratio (Rana et al., 2020). In the present study, the duration of oxygen therapy was shorter in patients treated with dexamethasone, which is consistent with the study of Rana et al.

In the present study, the frequency of hypokalemia and hyperglycemia was significantly higher in the methylprednisolone group than in the dexamethasone group, indicating a lower risk of dexamethasone for hypokalemia and hyperglycemia. Hyperglycemia is a common side effect of corticosteroid therapy that affects 20-50% of patients without a history of diabetes. Glucose levels are often elevated in patients with DM and previously controlled DM during corticosteroid therapy. Changes in carbohydrate metabolism, including insulin resistance and decreased peripheral glucose uptake, may explain the increase in hyperglycemia in patients treated with corticosteroids (Clore and Thurby-Hay, 2009). In the study of Donihi et al. (2006), the frequency of hyperglycemia and its multiple episodes were reported in 64% and 52% of patients under methylprednisolone treatment, respectively (Donihi et al., 2006). Hyperglycemia is an independent predictor of mortality in hospitalized COVID-19 patients. Because hyperglycemia may be exacerbated by systemic corticosteroids, its development may neutralize the benefits of corticosteroids and worsen prognosis in COVID-19 patients (Sardu et al., 2020, sardu et al 2020). Tocilizumab has been observed to be less effective on treatment in patients with hyperglycemia (Marfella et al 2020). In addition, oral or IV steroids with glucocorticoid properties, such as prednisolone and hydrocortisone, which are sometimes used to treat COPD, can increase renal potassium excretion and lead to hypokalemia (Veltri and Mason, 2015); hypokalemia is common in patients with COVID-19 pneumonia, is an independent predictor of the need for ICU and invasive ventilation and appears to be a biomarker of severe COVID-19 (Moreno-P et al., 2020). In addition, the known side effects of corticosteroids such as hyperglycemia and superimposed infection have been reported in COVID-19 patients (van Paassen et al., 2020). As well, the largest meta-analysis on low-dose corticosteroids in patients with sepsis did not show an increased risk of infection or gastrointestinal bleeding, although the risk of hyperglycemia, hypernatremia, and muscle weakness was found to increase (Annane et al., 2019). Due to the lower frequency of hypokalemia and hyperglycemia in patients treated with dexamethasone compared to methylprednisolone in the present study, this drug can be more confidently prescribed to the patients.

In our study, in patients treated with methylprednisolone, more hypokalemia was observed that can berelated to its greater mineralocorticoid effect, but due to the greater glucocorticoid effect of dexamethasone, the drug was expected to lead to more hyperglycemia that was not observed in our patients given the drug. In patients with COVID-19, there are multiple mechanisms leading to pulmonary edema that contribute to the severity of symptoms and mortality (Cui et al., 2021), and therefore it seems that methylprednisolone with greater mineralocorticoid effect and consequently more fluid retention, may be less effective than dexamethasone.

Although we observed better efficacy of dexamethasone in improving some of the complications of moderate to severe COVID-19, one of the limitations of our study was lack of including a control group to compare the outcomes and investigate the potentially positive efficacy of dexamethasone. Another limitation of our study was relatively small sample size (n: 143), which necessitates conducting larger controlled studies to achieve more conclusive results. In addition, it is possible that because healthcare providers were not blinded, at least some may have communicated the assigned treatment to patients.

In conclusion, although the present study showed better efficacy of dexamethasone compared to methylprednisolone in improving some moderate to severe COVID-19 complications including hospital stay length and oxygen therapy duration, the need for ICU and mortality in the two groups of patients were not significantly different. In addition, the frequency of hypokalemia and hyperglycemia was lower in patients receiving dexamethasone, which indicates better efficacy and lower risk of dexamethasone.

It is, however, recommended that similar studies be performed with a larger sample size and different doses of the two drugs to achieve more conclusive results.

Ethical considerations

All human procedures were reviewed and approved by the Shahrekord University of Medical Sciences Ethics Committees and complied with local ethics committee regulations (IR.SKUMS.REC.1399.288).

Funding

This study was supported by Shahrekord University of Medical Sciences, Shahrekord, Iran (grant no.: 3031).

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions:

ZH and AB made substantial contributions to the conception and design of the study and/or the acquisition, analysis and interpretation of data. MAS, MD, II, and HR contributed to collecting samples, performing experiments and analyzing the data. All authors contributed to drafting and critically revising the manuscript and providing important intellectual content; MAS, AB, and ZH revised the manuscript and approved the final version of the manuscript submitted. All authors read and approved the final version of the manuscript.

Acknowledgement:

The authors would like to thank the Clinical Research Development Unit of Hajar Hospital at Shahrekord University of Medical Sciences, Iran for their assistance in conducting this study.

Conflict of Interest

All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.

This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.

We confirm that there is no any conflict of interest.

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Appendix. Supplementary materialsArticle InfoPublication History

Accepted: July 5, 2022

Received in revised form: May 21, 2022

Received: November 28, 2021

Publication stageIn Press Journal Pre-ProofFootnotes

Research implications: Given the higher efficacy of dexamethasone compared to methylprednisolone for treatment of COVID-19, the health care system and physicians are recommended to consider dexamethasone in corticosteroid therapy for the disease.

Identification

DOI: https://doi.org/10.1016/j.ijid.2022.07.019

Copyright

© 2022 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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