The impact of different corticosteroids in hospitalised patients with severe COVID-19 pneumonia: a retrospective observational study

Sheridan Ramrattan¹, Amla Ramlal¹, Stanley Giddings^1
1Department of Internal Medicine, San Fernando General Hospital, Trinidad and Tobago

Corresponding Author:
Sheridan Ramrattan (MBBS, MRCP)
Email: [email protected]

DOAJ: 00ae9c8c19ab41cf81a0b34840c68e9c
DOI: https://doi.org/10.48107/CMJ.2024.03.005
Published Online: May 6, 2024

Copyright: This is an open-access article under the terms of the Creative Commons Attribution License which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.

©2024 The Authors. Caribbean Medical Journal published by Trinidad & Tobago Medical Association

ABSTRACT
Background: The COVID-19 pandemic created havoc on health care systems and economies worldwide. Corticosteroids have been shown to be effective in the management of COVID-19.

Methods: A retrospective observational study was conducted on 311 patients meeting the inclusion criteria at the Augustus Long Hospital, Trinidad and Tobago between July-December 2021. Data was classified into three treatment groups: low dose dexamethasone, high dose dexamethasone and methylprednisolone pulse therapy. The primary outcomes were the 28-day mortality and need for invasive mechanical ventilation and the secondary outcome was the length of hospital stay. The patient cohort was also classified into simple oxygen and high flow oxygen groups and a subgroup analysis was also performed.

Results: There were no significant statistical differences between age, gender, vaccination status and co-morbidities between the treatment groups. However, there were significant differences in the ethnic ratios amongst the high dose dexamethasone and methylprednisolone treatment groups (East Indians to Africans; 61.7%vs. 37%; 72.9% vs.25.4% respectively; p=0.02). In patients receiving simple oxygen on admission, those who were treated with low dose dexamethasone when compared to high dose dexamethasone and methylprednisolone, had the lowest 28-day mortality (15.3% vs. 40.9% vs. 40% respectively; p< 0.001), lowest need for IMV (0.7% vs. 9.1% vs. 40% respectively; p< 0.001) and the shortest length of hospital stay (median [IQR] days; 7[12-5], 11[22-7], 16[27-14] respectively; p< 0.001). In patients receiving high flow oxygen, those treated with methylprednisolone had the lowest 28-day mortality (45.8%), when compared to the high dose dexamethasone (59.5%) and low dose dexamethasone (81%) groups; however, these results were not statistically significant (p = 0.053).

Conclusion: In our study, patients receiving simple oxygen had better clinical outcomes when treated with low dose dexamethasone compared to higher dose corticosteroids. Methylprednisolone pulse therapy may be beneficial in patients requiring high flow oxygen; but further studies are needed.

INTRODUCTION
COVID-19 is an infectious disease caused by the SARS-COV-2 Virus.¹ It was first detected in Wuhan, China in late December 2019, after an outbreak of pneumonia cases. Since its emergence, the virus has spread vastly around the globe, and was declared as a pandemic by the WHO on the 11^th March, 2020.²

According to the National Health Institute, patients with SARS COV-2 infection can experience a range of clinical manifestations; which can be classified as follows: asymptomatic, mild, moderate, or severe illness requiring hospitalization, or critical illness with multi-organ failure needing invasive mechanical ventilation.^[3]  This study focuses on patients presenting with severe COVID-19, which is defined as an SpO2 < 94% on room air, a  ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%.³ 

The volume of patients who were presenting with severe and critical illness had placed an overwhelming burden on healthcare systems worldwide, resulting in shortages of PPE, medications, and ventilators. Not to mention, the worldwide economic crisis that was caused by the imposed lockdowns, in order to slow transmission of the virus.⁴ Furthermore, studies have shown a high prevalence of moderate depression, anxiety, and PTSD among healthcare workers, during the COVID-19 pandemic.⁵ Given the severe impacts of the pandemic, successful treatments are required for the reduction in mortality, need for invasive mechanical ventilation and length of hospital stay in patients presenting with severe COVID-19.

Severe COVID-19 occurs as a result of a dysregulated hyperinflammatory immune response. This leads to diffuse lung damage which can progress to respiratory failure and death. ⁶ Dexamethasone modulates inflammation-mediated lung injury in patients with COVID-19.⁷ The RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial, published in June 2020, showed that the use of low dose dexamethasone in patients requiring oxygen or ventilatory support, was associated with a reduction in 28-day mortality, need for invasive mechanical ventilation and length of hospital stay.⁸

Throughout the pandemic, different types and doses of corticosteroids have been implemented in the treatment of COVID-19 in different parts of the world. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group published a meta-analysis which showed that the use of corticosteroids (including dexamethasone, methylprednisolone and hydrocortisone) when compared to placebo, was associated with an overall reduction in the 28-day mortality, despite which steroid was used.⁹

Early on in the pandemic, it was hypothesised that higher dose corticosteroids may be more beneficial in the treatment of COVID-19 patients who were more clinically ill on admission. A randomised control trial (RCT) conducted in early 2021 in Spain, showed that high dose dexamethasone reduced clinical worsening when compared to low dose dexamethasone.¹⁰

However, in 2023, the RECOVERY group published an RCT which showed that higher dose dexamethasone was associated with an increased mortality when compared to low dose dexamethasone, in the treatment of hospitalised, hypoxic patients with COVID-19 who do not require ventilatory support.¹¹

Methylprednisolone pulse therapy was shown to decrease the activity of systemic inflammatory response, severity of coagulation disorders and contribute to the recovery of gas exchange lung function.¹² A meta-analysis published by Hong et al. included 12 studies (three of which were RCTs), that were conducted in multiple countries including: Pakistan, Iran, Egypt, Morocco, South Africa, Spain, Italy, Colombia and the USA. It was shown that when compared to low dose dexamethasone, methylprednisolone pulses can significantly reduce the systemic inflammatory response and has the potential to improve the prognosis in patients with severe COVID-19.¹³ Of note, the doses and treatment courses of methylprednisolone pulses were not consistent across the studies and there is still limited evidence, with no high powered RCT’s on the use of methylprednisolone pulse therapy in patients with severe COVID-19.

The use of low dose dexamethasone was incorporated as part of the usual care of patients presenting with severe COVID-19 at the Augustus Long Hospital; a secondary care institution for COVID-19 patients in Trinidad and Tobago. Higher dose corticosteroids were used in patients who were deemed to be more clinically ill, as determined by the clinical judgement of the attending physician. This study is aimed to compare low dose dexamethasone to higher dose corticosteroids (high dose dexamethasone and methylprednisolone pulse therapy) on 28-day mortality, need for invasive mechanical ventilation and length of hospital stay, within our cohort. These results will help in providing standardised care for patients with severe COVID-19 and thus help in preparation for future outbreaks.

METHODS
Study Design
This is a retrospective chart review conducted at the Augustus Long Hospital, Trinidad and Tobago. This hospital was part of the parallel health care system solely designated for the treatment of COVID-19 positive patients. Data was collected via convenience sampling, on patients who were admitted to the Adult Medical Ward between July-December 2021.

Study Population
The patient population included adults aged 18 years and over, who were SARS COV-2 PCR positive via nasopharyngeal swab, who presented with severe-COVID 19 pneumonia and treated with corticosteroids. Severe COVID-19 was defined as an SpO2 <94% on room air at sea level, pO2: FIO2 <300mmHg, a respiratory rate >30 breaths/min, or lung infiltrates > 50%.³

The exclusion criteria were as follows:

• Patients on chronic steroids and/or other immunosuppressants
• Patients with End Stage Renal Disease (eGFR > 15ml/min/1.73m²)
• Pregnant patients
• Palliative care patients
• Patients who died within 24 hours of admission
• Patients who were co-administered tocilizumab
• Patients requiring non-invasive/ invasive mechanical ventilation on admission (i.e. admitted to HDU or ICU on admission).

Given the aggressive nature of the pandemic at the time, the type, dose and duration of corticosteroid therapy was guided by physician clinical judgement and availability of medications. Steroid therapy was discontinued when patients no longer required supplemental oxygen.

All patients also received usual care, which included prophylactic anticoagulation, stress ulcer prophylaxis, antibiotic treatment for secondary infections, prone positioning when indicated and management of existing co-morbidities.

After reviewing the medical records, patients meeting inclusion criteria were categorized into the following three treatment groups:

1. Low dose dexamethasone 6mg once daily, which was stopped when clinically indicated.
2. High dose dexamethasone 20mg once daily for 5 days, followed by 10mg once daily for 5 days and if clinically indicated, followed by dexamethasone 6mg once daily until clinical improvement as seen fit by clinician.
3. Methylprednisolone pulse therapy: 250mg-1g for 3-5 days, followed by dexamethasone 6mg once daily until clinical improvement as seen fit by clinician.

An analysis was done between the three treatment groups.

In addition, there was another categorization of all the patients meeting inclusion criteria into the following two groups: simple oxygen group and high flow oxygen group. Simple oxygen was defined as oxygen flow rates up to 15L/min via nasal cannula, simple face masks, venturi masks or non-rebreather face masks. High flow oxygen was characterized as a non-rebreather mask with supplemental low flow nasal cannula; which was used as a substitute for a high flow nasal cannula device, attributable to limited resources during the pandemic.¹⁴ A subgroup analysis of the three treatment categories was done on the 2 oxygen groups.

The patients were divided into the oxygen groups because there was insufficient data to produce severity illness scores (e.g. SOFA, APACHE). As such, oxygen requirement on admission was used as a substitute for the severity of illness. Therefore, patients in the high flow oxygen group were deemed to be more clinically ill when compared to the simple oxygen group.

Data Collection
All data was collected from the patients’ medical records, which included patient demographics, medical co-morbidities, COVID-19 vaccination status, clinical parameters such as oxygen requirements on admission and type/dose/duration of steroid therapy received, as well as clinical outcomes, such as 28-day all-cause mortality, need for invasive mechanical ventilation and length of hospital stay. There were no duplicate records. A waiver of informed consent was granted by the South West Regional Health Authority Ethics Committee, as all data collected from patients’ medical records was de-identified.

Outcomes
The primary outcomes were the all cause 28-day mortality and the need for invasive mechanical ventilation. The secondary outcome was the length of hospital stay for patients who survived.

Statistical Analysis
All categorical variables were expressed as absolute frequencies and percentages. The primary outcomes; 28-day mortality and need for invasive mechanical ventilation, were analysed using Pearson Chi Square test. Continuous data was stated as a mean and standard deviation or a median with interquartile range (IQR). The symptom onset and length of stay were analysed using Kruskal Wallis test. The age between treatment groups was analysed using one-way ANOVA. A two-sided p-value of <0.05 was considered statistically significant. All data was analysed using IBM SPSS Statistics for Macintosh, Version 28.0. (Armonk, NY: IBM Corp).

RESULTS
A total of 463 patients admitted to the Augustus Long Hospital, Trinidad and Tobago between July-December 2021, were screened, and 152 were excluded from the study. Of the 311 patients who met inclusion criteria, 171(55%) belonged to the low dose dexamethasone group; 81(26%) to the high dose dexamethasone group and 59 (19%) to the methylprednisolone pulse therapy group. In addition, the 311 patients meeting inclusion criteria were also categorized into two oxygen groups; 229 patients in the simple oxygen group and 82 patients in the high flow oxygen group. A subgroup analysis was done comparing the three treatment options in each oxygen group, as shown in Figure 1.

Figure 1: Summary of participant data collection.

Table 1 represents the socio-demographical data of the sample population, which shows the average age was 60 years old in the low dose dexamethasone group, 59 years in the high dose dexamethasone group and 54 years in the methylprednisolone pulse group (p= 0.061).

Table 1: Comparison of baseline characteristics amongst the patient groups.

^a One Way ANOVA
^b Pearson Chi Square
^c Kruskal Wallis test

There was a slight male preponderance (53%) in the sample population, however, there were no significant differences in gender proportions between the treatment groups (p= 0.43). There were also no significant statistical differences in vaccination status and duration of symptom onset between the three treatment groups (p= 0.269; p= 0.603; respectively); with at least 80% of patients being unvaccinated and patients presented to hospital one week after the onset of viral symptoms.

Our overall sample population consisted of mainly East Indian (56.9%) and African (40.5%) ethnic groups, with a Mixed-Race minority (2.6%). A statistically significant difference in the ethnic ratio was noted amongst the three treatment groups (p=0.02). The low dose dexamethasone treatment group had a similar proportion of Africans (47.4%) and East Indians (49.1%), however, in the high dose dexamethasone and methylprednisolone groups, there were much higher proportions of East Indians to Africans (61.7% vs. 37%; 72.9% vs. 25.4%, respectively).

In the overall sample population, just over two thirds of the patients had medical co-morbidities, with the most common being DM and HTN, as shown in Table 1. The high dose dexamethasone and methylprednisolone groups had a larger proportion of DM patients when compared to the low dose dexamethasone group, which was statistically significant [53.1% vs. 52.5% vs. 37.4%; p= 0.024]. Table 2 shows the primary and secondary outcomes among the treatment groups. The difference in the all cause 28-day mortality was statistically significant and found to be the lowest in the low dose dexamethasone group (23.4%), followed by the methylprednisolone group (42.4%) and was the highest in the high dose dexamethasone group (49.4%). [p<0.001]. On the other hand, patients in the methylprednisolone group had the highest rate of requiring invasive mechanical ventilation and longest hospital stay when compared to the high dose dexamethasone and low dose dexamethasone groups {(39% vs. 8.6% vs. 1.2% respectively; p < 0.001); (median [IQR] (days) 7[12-5] vs. 11[20-8] vs.15[23-14]; p < 0.001)}.

Table 2: Comparison of outcomes amongst the steroid treatment groups.

^b Pearson Chi Square test
^c Kruskal Wallis test

As shown in Table 3, of the 311 included patients, 229 were in the simple oxygen group. In this group, patients were also categorized into the treatment groups as follows: 150 in the low dose dexamethasone group, 44 in the high dose dexamethasone group and 35 in the methylprednisolone group. In patients receiving simple oxygen on admission, those who were treated with low dose dexamethasone when compared to high dose dexamethasone and methylprednisolone, had the lowest 28-day mortality (15.3% vs. 40.9% vs. 40% respectively; p< 0.001), lowest need for IMV (0.7% vs. 9.1% vs. 40% respectively; p< 0.001) and the shortest length of hospital stay (median [IQR] days; 7[12-5], 11[22-7], 16[27-14] respectively; p< 0.001).

Table 3. Comparison of primary and secondary outcomes in patients receiving simple oxygen therapy.

^b Pearson Chi Square test
^c Kruskal Wallis test

The remaining 82 patients belonged to the high flow oxygen group; of which 21 were in the low dose dexamethasone group, 37 in the high dose dexamethasone group and 24 in the methylprednisolone group, as presented in Table 4. In patients receiving high flow oxygen, those who received methylprednisolone had the lowest 28-day mortality (45.8%), when compared to the high dose dexamethasone (59.5%) and low dose dexamethasone (81%) groups, however, these results were not statistically significant (p = 0.053). In addition, the methylprednisolone group had the highest need for IMV, when compared to high dose dexamethasone and low dose dexamethasone groups (37.5% vs. 8.1% vs. 2.2%, respectively; p= 0.002). There were no significant differences in the length of hospital stay between treatment groups.

Table 4: Comparison of primary and secondary outcomes in patients receiving high flow oxygen therapy.

^b Pearson Chi Square test
^c Kruskal Wallis test

DISCUSSION
SARS COV-2 is a b coronavirus, which comprises of the following 4 structural proteins: Spike(S), Membrane (M), Envelope (E) and Nucleocapsid (N).¹⁵ The spike protein is essential for the viral life cycle and is involved in viral receptor binding and fusion with the host cell.¹⁶ The viral spike protein enters the human host cell by attaching to the Angiotensin Converting Enzyme-2 (ACE-2) receptor.¹⁷ ACE-2 receptors are found in almost all human tissue, but are abundant in the lung, heart, kidney, ileum, thyroid and bladder and they are known to have a protective effect in helping to alleviate organ injury.¹⁷ SARS COV-2 spike protein attachment downregulates the ACE-2 receptor expression, which may be the source of acute lung injury and other organ injury in COVID-19 infection.¹⁷

After the virus enters the human host cell, viral replication occurs, and triggers programmed cell death in alveolar epithelial cells. This causes the early release of proinflammatory cytokines which recruit the cells of the innate immune system like alveolar macrophages, endothelial cells and dendritic cells. These cells become virally infected and further release cytokines. Dendritic cells serve as antigen presenting cells and assist with the recruitment of the adaptive immune response, which includes CD4+ and CD8+ T cells and B cells (antibody production). These immune responses induce viral infected cell death by cytotoxic T cells and antibody neutralization by immunoglobulin producing B cells, which in turn should cause successful clearance of SARS COV-2 from the lungs.¹⁸

However, in some patients with COVID 19 infection, a hyperactive immune response can occur which leads to an uninhibited release of cytokines. This is termed a “cytokine storm” and causes severe lung damage leading to Acute Respiratory Distress Syndrome (ARDS), multi-organ failure and death. Some of the key pro-inflammatory cytokines involved in propagating the cytokine storm include: IL-6, IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), IFN- γ, inducible protein (IP)-10, TNF-α, MCP-1 and macrophage inflammatory protein (MIP)-1α.¹⁹ Thus, therapies dampening the overactive immune response in these patients would be beneficial in decreasing the severity of COVID-19 and improving survival rates.

Glucocorticoids modulate inflammation-mediated lung injury, by suppression of neutrophil migration, reversal of capillary permeability, decreasing lymphocyte colony proliferation, inhibiting cytokines, increasing levels of surfactant, and improving pulmonary circulation.⁷

Dexamethasone has strong anti-inflammatory properties and minimal mineralocorticoid effect on sodium and fluid balance.⁷ Its use was recommended by the RECOVERY trial, published in 2020, which showed that the use of low dose dexamethasone (6mg) once daily for up to 10 days in patients requiring oxygen therapy, resulted in a reduction in 28-day all-cause mortality, duration of hospital stay and need for progressing to ICU care, when compared to usual care only.⁸

In 2023, the RECOVERY Collaborative Group published its randomised control trial comparing low dose dexamethasone 6mg for up to 10 days with high dose dexamethasone 20mg for 5 days followed by 10mg for 5 days, in hypoxic patients not requiring ventilatory support. The strengths of this RCT were its large sample size of 1272 participants and the heterogenous population, as centres from the UK, Asia and Africa were included. The trial showed that the use of high dose steroids increased the mortality for patients with COVID-19 who are receiving simple oxygen.¹¹ Our study reproduced similar findings and showed that in patients only requiring simple oxygen, those treated with low dose dexamethasone when compared to the higher corticosteroid groups, had the lowest mortality, need for invasive mechanical ventilation and shortest hospital length of stay. This can be attributed to excessive dampening of protective immune responses and poorer glycaemic control, thus leading to increased superimposed infections and worse outcomes in the higher corticosteroid groups.

It was shown in animal models that methylprednisolone has better lung tissue to plasma ratios when compared to dexamethasone and may be more effective in reducing lung injury.²⁰ As such, our study showed that in the high flow oxygen group, patients receiving methylprednisolone pulse therapy were noted to have the lowest mortality when compared to the high and low dose dexamethasone groups (45.8% vs. 59.5% vs. 81% respectively; p= 0.053). However, these results were not statistically significant, as the study may not have been adequately powered to detect a difference if one existed.

Similarly, a meta-analysis by Hong et al., showed that methylprednisolone can reduce the systemic inflammatory response when compared to dexamethasone, and at moderate doses in certain patients, can be more beneficial than dexamethasone in the treatment of patients with severe COVID-19. ^[13] However, due to a lack of high powered RCTs comparing methylprednisolone to dexamethasone in the literature, this meta-analysis consisted of mostly non-RCT studies with substantial clinical heterogeneity. Therefore, higher quality RCTs with large sample sizes are needed to confirm any benefit and optimal dosing of methylprednisolone pulse therapy in the treatment of severe COVID-19.

In our study, the ethnic groups consisted mainly of Africans and East Indians with a Mixed-Race minority. Notably, there was a much higher proportion of East Indians to Africans in the high dose dexamethasone and methylprednisolone treatment groups, which was statistically significant (61.7% vs. 37%; 72.9% vs. 25.4% respectively; p= 0.02). In addition, our population cohort consisted of a higher proportion of diabetic patients in the high dose dexamethasone and methylprednisolone groups when compared to the low dose dexamethasone group (53.1% vs. 52.4% vs. 37.4% respectively; p=0.024).

Sze et al. stated after systematic review and meta-analysis, the inadequacy of data on ethnicity and its contribution to the increased risk of COVID-19 morbidity and mortality, but commented on its relationship between Africans and Asians and poor clinical outcomes as compared to Caucasians with Asians having a higher incidence of intubation.²¹ A similar article by Pan et al., alluded to the increased risk of cardiovascular disease within the Asian population contributing to worsening outcomes, coupled with the expression of ACE-2 receptors as the entry point for SARS-CoV-2, and its location within the myocardium.²² Also mentioned was the high incidence of persons with DM and HTN within the Asian population, possibly contributing to the increased morbidity and mortality.²² In our study, the high proportion of East Indians and high incidence of DM in the high dose dexamethasone and methylprednisolone treatment groups may have contributed to the much higher mortality rates in these groups compared to low dose dexamethasone group.

Limitations
In this study, convenience sampling was used which increases the potential for bias. There was a large sample size in the low dose dexamethasone group, but a much lower number of patients in the high dose dexamethasone and methylprednisolone groups. This reduces statistical power in the analysis.

There was insufficient data available to produce severity illness scores like SOFA or APACHE. As such, the amount of oxygen needed on admission to hospital was used as a surrogate for the severity of illness; with patients needing higher oxygen requirements being deemed as more clinically ill. Therefore, our cohort was also categorized into simple and high flow oxygen groups and a subgroup analysis was performed.

This study was conducted at the peak of the COVID-19 pandemic in Trinidad and Tobago, where there were limited resources due to an overburdened healthcare system at that time. This resulted in rationed high flow nasal cannula devices, ventilators and ICU beds. As such, a non-rebreather mask with supplemental low flow nasal cannula was used as an alternative to a high flow nasal cannula device. This option was used based on evidence from a retrospective study conducted in the emergency department of two tertiary hospitals in Malaysia, which showed that a non-rebreather mask with supplemental low flow oxygen when compared to high flow nasal cannula, had similar improvement in oxygenation at 2 hours and no significant differences in long term outcomes.¹⁴ However, this study had a small sample size of 110 patients and this statement would need to be confirmed with high powered RCTs.

It is also important to note that not all patients who required escalation of care to invasive mechanical ventilation would have gotten it, due to the aforementioned constraints. Therefore, the results under-represent the actual numbers of patients requiring invasive mechanical ventilation throughout the treatment groups.

Conclusion
In our study population, it was shown that in patients receiving simple oxygen, the use of low dose dexamethasone was associated with better clinical outcomes when compared to higher dose corticosteroids. However, in patients receiving high flow oxygen, methylprednisolone pulse therapy may be more beneficial; but this needs to be analysed with high powered randomised control trials.

Ethical approval statement: The approval for performing and publishing this study was permitted by the South West Regional Health Authority Ethics Committee.
Financial disclosure or funding: Not applicable.
Conflict of interest: There was no conflict of interest in this study.
Informed consent: A waiver of informed consent was granted by South West Regional Health Authority Ethics Committee, as all collected data was de-identified.
Author contributions: Dr. Sheridan Ramrattan contributed towards conception and design of the study, data collection, statistical analysis and interpretation of all data collected and drafting final manuscript. Dr. Amla Ramlal contributed towards conception and design of the study, data collection and drafting final manuscript. Dr. Stanley Giddings contributed towards conception and design of the study and revising final manuscript. All authors read and approved the final manuscript.

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