INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in Wuhan, China, in late 2019, led to the global COVID-19 pandemic, with over 600 million cases reported by mid-2023.[1] COVID-19 symptoms range from mild to severe, particularly affecting older adults and those with comorbidities.[2,3] The disease progresses through pulmonary inflammation, and a hyperinflammatory cytokine storm phase characterized by elevated interleukin (IL-6), C-reactive protein (CRP), and D-dimer levels[4] [Table 1]. Untreated cytokine storms can cause multi-organ failure, with clinical outcomes influenced by timely interventions.[5]

Table 1: The severity of COVID-19 disease.

Clinical category Definition of COVID-19 severity Mild disease Mild symptoms, with or without pneumonia visible on radiographic examination Moderate disease Presence of respiratory symptoms and fever, accompanied by pneumonia detected on chest radiograph Severe disease Dyspnea, respiratory rate≥30 breaths/min, oxygen saturation (SpO2) ≤93%, arterial oxygen partial pressure to fractional inspired oxygen ratio (PaO2/FiO2) <300, and/or pulmonary infiltrates involving more than 50% of the lung field. Critically ill Respiratory failure requiring mechanical ventilation, septic shock, multi-organ failure, necessitating ICU admission

COVID-19 progresses through stages starting with a 2–14-day incubation, followed by constitutional symptoms such as fever, fatigue, and headache after viral replication[6,7] [Figure 1]. The pulmonary inflammatory phase includes pneumonia with or without hypoxia. The late phase involves a hyperinflammatory cytokine storm marked by elevated IL-6, CRP, erythrocyte sedimentation rate (ESR), D-dimer, lactate dehydrogenase (LDH), and ferritin levels, often leading to immune dysregulation and multi-organ failure if untreated.[5,8,9] Onset and duration vary depending on the cause and treatment.[5] Late-stage cytokine storm manifestations in severe COVID-19 patients often overlap, leading to acute lung injury and diffuse alveolar damage.[9,10] This hyperinflammatory state contributes to pulmonary fibrosis, acute respiratory distress syndrome (ARDS), and increased mortality.[8,11] The pathological progression underscores the importance of early recognition and targeted interventions to mitigate lung damage and improve outcomes in critically ill patients.[5]Figure 2 illustrates these overlapping clinical features and disease severity patterns.

Figure 1: The course of COVID-19.

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Figure 2: Clinical picture of cytokine storm.

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Current COVID-19 management focuses on supportive care, including oxygen therapy and ventilation as needed, combined with adjunctive treatments such as antivirals (e.g., remdesivir, paxlovid), IL-6 inhibitors (e.g., tocilizumab), corticosteroids, and immunomodulators.[12,13] Antimalarials like hydroxychloroquine are no longer recommended due to a lack of efficacy.[14] Treatment protocols continue to evolve with emerging variants and clinical evidence to optimize patient outcomes.

Corticosteroids are synthetic glucocorticoids with anti-inflammatory and immunosuppressive effects, acting by modulating lymphocyte activity and reducing pro-inflammatory cytokine expression [Figure 1].[15] They penetrate cell membranes and bind to cytoplasmic receptors, forming complexes that translocate to the nucleus. There, they interact with glucocorticoid response elements in DNA, altering gene transcription and immune responses.

Corticosteroids are widely used to treat inflammatory and immune-related diseases due to their potent anti-inflammatory and immunosuppressive properties.[16] Although corticosteroids share similar chemical structures and clinical effects, they vary slightly in their tendency to cause salt and water retention.[17] Their anti-inflammatory efficacy and side effect profiles are generally comparable. Distinguishing different types of corticosteroids, including equivalent dose potency, duration, and mineralocorticoid (salt–water retention) activity, is summarized in Table 2.[16,17]

Table 2: Corticosteroids relative potencies and properties.

Medication Anti-Inflammatory potency (relative) Equivalent potency (mg) Duration of effect (h) Sodium retaining potency (relative) Short acting   Hydrocortisone 1 20 8–12 1 Intermediate   Methylprednisolone 5 4 18–36 0.5 Long-acting   Dexamethasone 25 0.75 >36 0

Dexamethasone has a more potent anti-inflammatory effect than methylprednisolone.

The WHO advises corticosteroids only for severe COVID-19 cases with ARDS, sepsis, or septic shock, cautioning early use due to possible viral load increase.[12,18] Studies show methylprednisolone may benefit ARDS patients by reducing inflammation and intensive care unit (ICU) stay.[19,20] The RECOVERY trial found that dexamethasone reduces 28-day mortality in patients needing respiratory support.[21,22] Comparative data on corticosteroids for COVID-19 remain limited, particularly in this region; therefore, this study aims to evaluate and compare the effects of methylprednisolone, dexamethasone, and hydrocortisone on mortality, length of hospital stay, respiratory support requirements, and inflammatory markers.

MATERIAL AND METHODS

A single-site, retrospective observational study was conducted to compare the effectiveness of methylprednisolone, dexamethasone, and hydrocortisone in patients with severe COVID-19. Patient records were reviewed for this analysis. The study took place at the General Network of Healthcare Providers Hospitals in Jeddah, Saudi Arabia, a facility offering both outpatient and inpatient services.

All patients diagnosed with severe COVID-19 and treated with one of the three corticosteroids between February 2020 and December 2020 were included. A non-probability sampling technique was used for data collection. The study participants were selected based on their availability and willingness to participate during the study, rather than by probability-based random sampling. The sample size was calculated using G*Power software, yielding a total of 74 patients.

Inclusion criteria were patients aged 18 years or older who received one of the following treatment regimens: methylprednisolone 40 mg intravenous (IV) twice daily for at least 3 days, dexamethasone 6 mg IV once daily for at least 7 days, or hydrocortisone 50 mg IV every 6 h for at least 7 days. Patients who received any corticosteroids other than the three specified were excluded from the study.

Data were extracted from patients’ electronic medical records and included demographic information, admission details, diagnosis, disease severity, corticosteroid used, dosage regimen, and duration of treatment. Relevant laboratory results were also collected.

The primary outcome measures were mortality and inflammatory markers, including CRP, ESR, D-dimer, LDH, serum ferritin, and procalcitonin levels. Data analysis was performed using SPSS software (Version 22). Comparisons between groups were conducted using paired t-tests, and a P < 0.05 was considered statistically significant.

This study was retrospective and non-interventional, and all data were handled with strict confidentiality. Patient names and identifiers were anonymized and not disclosed. The study was approved by the Institutional Review Board of Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia (IRB No. 015CPP-PG-11112020, dated January 21, 2021).

RESULTS

A study was conducted on 74 patients admitted to the ICU unit of GNP Hospital. Out of 74 patients, 46 received methylprednisolone, 21 received dexamethasone, and 7 received hydrocortisone [Figure 3]. The mean age of the methylprednisolone, dexamethasone, and hydrocortisone groups was 55, 53, and 63 years, respectively.

Figure 3: Chemical structures of hydrocortisone, methylprednisolone, and dexamethasone.

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Of all cases, there were 28 (37.8) females, 46 (62.2) males included in the study received methylprednisolone, 32 (70.2) males and 14 (29.8) females, dexamethasone 11 (52.4) males and 10 (47.6) females, and hydrocortisone 3 (42.9) males and 4 (47.1) females. All groups were matched for comorbid conditions such as pre-existing diabetes mellitus, hypertension, and dyslipidemia, as described in Table 3 and Figure 4.

Table 3: Basic characteristics of the patients.

Characteristics Methylprednisolone (n=46) Dexamethasone (n=21) Hydrocortisone (n=7) Age (M±SD) 56.43±12.3 53±16.3 64±6.5 LOS (M±SD) 17.85±9.85 16.52±10.90 19.43±10.26 Weight (M±SD) 91.59±17.0 88±22.4 95±18.4 Gender   Female 14 (29.8) 10 (47.6) 4 (57.1)   Male 32 (70.2) 11 (52.4) 3 (42.9) Comorbidities   Diabetes mellitus 24 (51.1) 12 (57.1) 0   Hypertension 22 (46.8) 9 (42.9) 0   Dyslipidemia 4 (8.5) 3 (14.3) 0   Heart disease 3 (6.4) 3 (14.3) 1 (14.3)   CKD 3 (6.4) 4 (19.1) 0   Asthma 1 (2.1) 0 0   Breast cancer 1 (2.1) 0 0   COPD 2 (4.3) 0 0   Hypothyroidism 3 (6.4) 0 0   Medically free 9 (19.1) 2 (9.5) 1 (14.3)   Not known 8 (17.0) 3 (14.3) 6 (85.7) Figure 4: Co-existing disease conditions.

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Most patients who received methylprednisolone or dexamethasone had co-existing diabetes and hypertension, along with other comorbidities such as dyslipidemia, heart disease, and chronic kidney disease [Figure 4]. While viral pneumonia was the primary diagnosis, some patients also received these drugs for ARDS, lung fibrosis, and secondary bacterial infections [Table 4].

Table 4: Initial diagnosis of the patients.

Diagnosis Methylprednisolone Dexamethasone Hydrocortisone n (%) n (%) n (%) Viral pneumonia 46 100 21 100 7 100 ARDS 25 53.2 15 71.4 5 71.4 Lung fibrosis 6 12.8 1 4.8 1 14.3 Secondary bacterial infection 14 29.8 7 33.3 1 14.3

ARDS was observed in a significant number of patients across all corticosteroid groups, with higher rates in those receiving dexamethasone and hydrocortisone, while lung fibrosis was less common [Table 4]. Secondary bacterial infections developed within 5–7 days in all groups, and although respiratory and fever symptoms were predominant, gastrointestinal symptoms were noted, especially among patients treated with hydrocortisone [Table 5 and Figure 4].

Table 5: Associated symptoms with COVID-19.

Symptoms Methylprednisolone Dexamethasone Hydrocortisone n (%) n (%) n (%) Cough 40 85.1 20 95.2 0 0 Fever 42 89.4 20 95.2 0 0 SOB 46 97.9 21 100 0 0 Anorexia 5 10.6 3 14.3 0 0 Nausea 7 14.9 3 14.3 2 28.6 Vomiting 6 12.8 3 14.3 2 28.6 Diarrhea 6 12.8 5 23.8 1 14.3 Fatigue 2 4.3 2 9.5 1 14.3

Most patients in the methylprednisolone and dexamethasone groups experienced fever and respiratory symptoms, while gastrointestinal symptoms were more frequent in the hydrocortisone group. Inflammatory markers were used to assess disease severity, and the study compared how different corticosteroids affected these markers and improved oxygen saturation [Figure 4 and Table 6].

Table 6: Study the effect of corticosteroids on inflammatory markers and oxygen saturation.

Markers ∆ Methylprednisolone Dexamethasone Hydrocortisone Mean SD SEDM P-value Mean SD SEDM P-value Mean SD SEDM P-value CRP 30.25 43.44 7.67 0.003 16.11 30.26 7.81 0.058 14.80 36.3 25.7 0.66 ESR 14.06 29.16 5.15 0.030 26.31 354.9 4.59 0.79 14.00 5.65 4.00 0.17 LDH 315.36 408.58 71.12 0.008 367.53 1257.8 88.7 0.77 −56.00 98.9 57.1 0.43 Ferritin 413.66 572.73 99.70 0.042 16.11 30.26 314.46 0.26 −355.9 571 403.9 0.54 PCT 3.69 18.21 3.17 0.262 2.14 6.10 0.516 0.21 −0.030 0.070 0.040 0.53 D-Dimar 19.20 83.46 14.52 0.219 −1.20 17.79 1.52 0.18 0.157 3.24 1.87 0.94 O2 sat −6.51 10.15 1.71 0.001 −3.54 3.07 0.928 0.003 −9.50 0.707 0.500 0.03

Patients treated with methylprednisolone showed significant reductions in CRP, ESR, LDH, and serum ferritin levels, along with improved oxygen saturation, indicating better control of inflammation and disease severity [Figure 5]. Dexamethasone showed moderate improvement in CRP and oxygen requirement, whereas hydrocortisone showed no significant changes in inflammatory markers or oxygenation [Table 6].

Figure 5: Mechanism of action of methylprednisolone.

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Out of the 74 patients, most developed lung injury and required mechanical ventilation. Multi-organ failure was also observed among critically ill patients.

The study evaluated the effectiveness of different types of corticosteroids in preventing disease progression in critically ill COVID-19 patients. The results are summarized in Table 7.

Table 7: Critical ill patients on MV, poor prognosis, and multi-organ failure.

Critical ill patients n Methylprednisolone Dexamethasone Hydrocortisone (%) n (%) n (%) Mechanical support MV 23 48.9 13 61.9 5 71.4 ECMO 1 2.1 1 4.8 Prognosis Septic shock 8 17.0 4 19.0 3 42.9 Cardiogenic shock 2 9.5 Organ dysfunction Lung 37 78.7 18 85.7 7 100 Heart 8 17 7 33.3 2 28.6 Kidney 10 21.3 7 33.3 3 42.9 Liver 2 9.5 Survival Death 12 25.5 8 38.1 5 71.4 Improved 20 42.6 8 38.1 2 28.6 Stationary ∆ 14 29.8 5 23.8

Critically ill COVID-19 patients requiring ventilatory support were highest in the hydrocortisone group (71.4%), followed by dexamethasone (61.9%) and methylprednisolone (48.9%). Septic shock and 28-day mortality were also more frequent in the hydrocortisone group, suggesting worse outcomes possibly due to secondary infections, older age, and existing comorbidities [Table 7]. Most patients developed lung injury (ARDS), with cardiac and kidney injuries observed across all corticosteroid groups, while liver injury occurred only in two patients receiving dexamethasone. Table 8 outlines the associations between corticosteroid type, mechanical ventilation, age, and vasopressor use among critically ill patients [Table 8].

Table 8: Association between different types of corticosteroids and mortality.

Number of deaths/total number of patients Methylprednisolone (%) Dexamethasone (%) Hydrocortisone (%) MV   Yes 5/23 (10.8) 7/13 (33.3) 5/6 (71.4)   No 7/23 (15.2) 1/8 (4.7) 0/1 Age   ≤60 5/31 (10.8) 3/12 (14.2 1/2 (14.2   >60 7/15 (15.2) 5/9 (23.8) 4/5 (57.1) Gender   M 32 (69.5) 11 (52.3) 3 (42.8)   F 14 (30.4) 10 (47.6) 4 (57.1) LOS (mean) 17.8 16.52 19.43 Vasopressors ∆ 14/46 (30.4) 10/21 (47.6) 5/7 (71.4)

Among the 74 patients studied, the methylprednisolone group showed higher survival with a 22.5% absolute reduction in mortality compared to dexamethasone (10.8% vs. 33.3%), though no significant difference was seen in patients over 60 years old. Mechanical ventilation was associated with higher death rates, especially in the hydrocortisone group, where 71.4% of ventilated patients died, and overall mortality was highest in older patients, particularly those receiving hydrocortisone [Table 8].

DISCUSSION

At the end of 2019, the emergence of SARS-CoV-2 led to a global pandemic, posing unprecedented challenges to healthcare systems worldwide. To date, no universally effective antiviral treatment has been established, although several therapeutic strategies, including corticosteroids, have demonstrated clinical benefits in certain patient populations.[23] The clinical progression of severe COVID-19 typically involves an initial viral replication phase, followed by an inflammatory pulmonary phase and a hyperinflammatory cytokine storm phase, which is associated with acute lung injury and ARDS.[9,24] This dysregulated immune response contributes to multi-organ failure and increased mortality if not effectively controlled.

Although the exact immunopathology driving the cytokine storm in COVID-19 remains under investigation, corticosteroids have become a cornerstone of treatment to modulate this hyperinflammation.[25] Controlling the cytokine storm is essential to prevent clinical deterioration and improve outcomes in severe COVID-19. While corticosteroids have been used in both non-severe and severe cases, their benefit–risk profile depends on timing, dosage, and patient characteristics.[26] Our study focused on severe COVID-19 cases, evaluating the comparative efficacy of different corticosteroids in this high-risk population.

The landmark RECOVERY trial demonstrated that dexamethasone reduces 28-day mortality in hospitalized COVID-19 patients requiring oxygen therapy or mechanical ventilation, with an absolute mortality reduction of 2.8% (22.9% vs. 25.7%) and an age-adjusted rate ratio of 0.83 (95% confidence interval, 0.75–0.93).[25] This benefit was limited to patients requiring respiratory support, underscoring the importance of patient selection for corticosteroid therapy.

Recent retrospective studies have suggested that methylprednisolone, due to its pharmacologic properties, may confer additional benefits compared to dexamethasone, particularly in mechanically ventilated patients. Ko et al. reported a 42% reduction in mortality with adequately dosed methylprednisolone (1 mg/kg/day for ≥3 days) versus dexamethasone in mechanically ventilated COVID-19 patients.[27] Similarly, the GLUCOCOVID trial indicated that short courses of methylprednisolone reduce ICU admission and progression to mechanical ventilation, with significant decreases in inflammatory markers such as CRP.[28]

Supporting evidence from multicenter observational cohorts also demonstrated that corticosteroid use in critically ill COVID-19 patients correlates with lower mortality and shorter hospital stays without increasing secondary infections.[29,30] Importantly, corticosteroids appear most beneficial when initiated in the inflammatory phase of COVID-19, particularly in patients with hypoxemia and systemic inflammation.[31]

While earlier coronavirus outbreaks (SARS-CoV-1 and middle east respiratory syndrome (MERS)) presented mixed results regarding corticosteroid efficacy, recent meta-analyses specific to COVID-19 have confirmed that corticosteroids reduce mortality and progression to mechanical ventilation in severe cases.[32] The heterogeneity in corticosteroid types, dosages, and timing across studies highlights the need for individualized therapeutic approaches.

Our study adds to this evolving evidence by demonstrating that methylprednisolone was associated with a greater mortality reduction (42.6%) compared to dexamethasone (38.1%), especially among patients requiring mechanical ventilation. This improved outcome may be attributed to methylprednisolone’s higher anti-inflammatory potency and greater efficacy in reducing inflammatory biomarkers such as CRP, ESR, LDH, and serum ferritin [Table 6]. In addition, methylprednisolone’s shorter biological half-life (24–36 h) compared to dexamethasone (36–54 h) may allow more flexible dosing and titration in critical illness.[33] Both methylprednisolone and dexamethasone showed significant clinical benefits in ventilated patients, reinforcing corticosteroids as a critical intervention to prevent disease progression and improve survival. Nonetheless, our study has limitations, including its single-center retrospective design and relatively small sample size of 74 patients. Larger multicenter randomized controlled trials are needed to confirm these findings, optimize corticosteroid regimens, and evaluate long-term outcomes.

Finally, corticosteroids remain essential in managing severe COVID-19, particularly in patients experiencing cytokine storm and respiratory failure. Methyl prednisolone may offer superior anti-inflammatory effects and survival benefits compared to dexamethasone in selected patients, particularly those on mechanical ventilation. However, further high-quality studies are warranted to define optimal corticosteroid use and improve patient care in this ongoing pandemic.

CONCLUSION

The inflammatory phase of COVID-19 often necessitates the use of corticosteroids; however, there is ongoing debate regarding the optimal choice among the commonly used agents – dexamethasone, methylprednisolone, and hydrocortisone. To evaluate the utilization, efficacy, and safety of these corticosteroids, we conducted an observational study from February to December 2020 involving 74 COVID-19 patients treated with one of these agents. Both methylprednisolone and dexamethasone demonstrated significant benefits in patients requiring mechanical ventilation. Notably, methylprednisolone showed superior activity in reducing inflammatory markers such as CRP and lactate LDH, with P-values of 0.003 and 0.008, respectively. Furthermore, methylprednisolone was associated with a 22.5% absolute reduction in mortality compared to dexamethasone, although this survival benefit was limited to mechanically ventilated patients. Larger, more detailed studies are needed to validate these findings.