Effect of methylprednisolone in reducing severe COVID-19 and mortality in high-risk patients: A retrospective study

Abstract

Introduction:

The treatment of COVID-19 patients, especially high-risk patients, remains a large challenge. Glucocorticoids have been accepted as effective medicines for severe COVID-19. However, the glucocorticoid usage guidelines do not cover all the indications for high-risk patients.

Objective:

To identify more effective treatments for high-risk patients with COVID-19, this retrospective study analyzed routine epidemiological, clinical, and laboratory data from 33 high-risk patients with COVID-19 in Beijing Gobroad Boren Hospital, Beijing, China, most of whom responded well to treatment.

Methods:

Severe acute respiratory syndrome coronavirus-2 infection was confirmed via real-time reverse transcriptase polymerase chain reaction assays. Outcome measures such as duration of mechanical ventilation, intensive care unit length of stay, and 28-day mortality were analyzed. Patients were divided into two groups: mild to moderate COVID-19 (n = 26) and severe COVID-19 (n = 7). Chest computed tomography images were used to guide methylprednisolone administration or withdrawal.

Results:

Upon intensive care unit admission, 12.1% of patients were mechanically ventilated with an average partial pressure of oxygen/fraction of inspired oxygen(PaO₂/FiO₂) ratio of 279 ± 146. No coinfections with other endemic viruses were observed. The duration of mechanical ventilation was 16 days (interquartile range: 8–28); the intensive care unit length of stay was 11 (interquartile range: 2–33) days; and the 28-day total mortality was 3.0%.

Conclusion:

Multivariate regression analysis revealed that low-dose, timely methylprednisolone administration was associated with a lower severe COVID-19 rate and mortality in high-risk patients. For high-risk patients, once there are ground-glass opacities (GGO) in the computed tomography image, continuous and low-dose methylprednisolone administration promotes inflammation remission and protects them from severe COVID-19 or mortality.

Keywords

Methylprednisolone severe COVID-19 high-risk patients CT image

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed more than 6.9 million patients worldwide (as of December 20, 2023) and has been a persistent threat to high-risk patients (https://covid19.who.int). Multiple vaccines, monoclonal antibodies, and antiviral drugs have been suggested as treatments for SARS-CoV-2 infection; however, for high-risk patients, most of these measures do not effectively reduce the risk of progression to severe disease or are too expensive or logistically difficult to treat widely. There is still a lack of guidance for special populations with COVID-19, such as immunocompromised individuals.¹

Glucocorticoids, including hydrocortisone and methylprednisolone, are now recommended for patients with severe COVID-19, including those with COVID-19-related acute respiratory disease syndrome (ARDS).² The WHO clinical practice guidelines provide strict and limited indications for corticosteroid use, including low oxygen saturation (less than 90%) and rapid pneumonia progression in computed tomography (CT) images of patients with COVID-19.³ However, in high-risk patients with COVID-19, who have a relatively high mortality rate, the indications for glucocorticoid usage remain to be determined.

CT examination is very important for monitoring disease progression and evaluating therapeutic efficacy. The bilateral distribution of ground-glass opacities with or without consolidation in the posterior and peripheral lungs is considered the hallmark of COVID-19.⁴ The crazy paving pattern is also considered a typical pneumonia progression CT imaging feature of COVID-19.⁵ Pneumonia lesions were classified into four stages on chest CT: early, progressive, peak, and absorption. However, the roles of CT images in guiding glucocorticoid usage are largely unclear and of great interest.

The objective of this retrospective study was to summarize the clinical data examining the use of methylprednisolone, which is mostly guided by CT images, in high-risk patients with COVID-19. We examined whether the effects of methylprednisolone are consistent across methylprednisolone dosing regimens, the time of methylprednisolone initiation, and the duration of therapy. Our data suggest that early and low-dose methylprednisolone administration is beneficial in high-risk patients with COVID-19.

Materials and methods

Study design and patients

We retrospectively analyzed high-risk patients with COVID-19 admitted to our intensive care unit (ICU) from March 20, 2022, to May 31, 2023. In total, 33 high-risk inpatients were enrolled (Table 1). The studies were included per the inclusion and exclusion criteria. We included patients whose clinical efficacy and adverse effects of methylprednisolone with standard therapy in the treatment of COVID-19 clearly reported on at least one relevant outcome, including days of treatment with mechanical ventilation (MV), length of hospital stay, all-cause mortality, and other adverse events. In addition, patients need to be at increased risk of severe disease, which we have defined in Table 2. Studies were excluded if they did not report the efficacy of methylprednisolone in the treatment of COVID-19 or if they did not have CT images. Alternatively, they were unable to provide informed consent. SARS-CoV-2 infection was confirmed via real-time polymerase chain reaction (RT-PCR) assays performed on nasopharyngeal swabs via a QuantiNova Probe RT-PCR kit (Qiagen, GmbH, Germany) in a Light Cycler 480 real-time PCR system (Roche, Basel, Switzerland) as described in detail elsewhere.⁶ The main outcome variable was in-hospital mortality. Other usual outcome measures, such as duration of MV, ICU stay, and hospital length of stay, were integrated into the analysis. In addition, we also enrolled 18 fully vaccinated COVID-19 outpatients as vaccination control. These outpatients were enrolled from March 20, 2022, to May 31, 2023, and they met the high-risk COVID-19 definition except that they are fully vaccinated. Written informed consent was obtained from all subjects. The study was approved by the ethical committee of Beijing Gobroad Boren Hospital.

Table 1.

Main parameters of high-risk patients with COVID-19.

Parameters	Total patients (n = 33)	COVID-19 (n = 26)	Severe COVID-19 (n = 7)
General characteristics
Age (years)	61.6 ± 20	59.6 ± 21.7	68.9 ± 9.3
Sex (male n, %)	14, 42.4%	10, 38.5%	4, 57.1%
Smokers (n, %)	2, 6.1%	2, 7.7%	0, 0%
Complications
Hematological malignancies (n, %)	17, 51.5%	12, 46.2%	5, 71.4%
Solid carcinoma (n, %)	7, 21.2%	7, 26.9%	0, 0%
Others (n, %)	9, 27.3%	7, 26.9%	2, 28.6%
Outcome measures
MV (n, %)	4, 12.1%	0, 0%	4, 57.1%
PaO₂/FiO₂ (on d0, mean + standard deviations (SD))			279 ± 146
ICU length of stay (days IQR)	11 (2–33)	9 (2–33)	19 (2–43)
Hospital length of stay (days IQR)	17 (5–84)	14 (2–35)	31 (7–84)
Symptoms
Caugh (n, %)	30, 90.9%	23, 88.5%	7, 100%
Fever > 38.5°C (n, %)	27, 81.8%	20, 76.9%	7, 100%
Shortness of breath (n, %)	16, 48.5%	9, 34.6%	7, 100%
Myalgia (n, %)	3, 9.1%	3, 11.5%	0, 0%

Table 2.

Definition of high-risk patients for severe COVID-19 or mortality.

Age	>65 years old
Living environment	Living in nursing home or living in long-term care facility
COVID-19 vaccine	No vaccination or no response to COVID-19 vaccine
Underlying diseases	Cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, diabetes complications, neurocognitive impairment, obesity, cancer, cystic fibrosis, immunocompromised, liver diseases (especially hepatic sclerosis), pregnancy and sickle cell disease, organ transplant recipients, other diseases that require taking immunosuppressive drugs, etc.

Definitions

The WHO severity criteria for COVID-19 were used.⁷ Data from the European Centre for Disease Prevention and Control (ECDC) were obtained to define risk factors and groups for severe COVID-19.⁸

Data collection and therapeutic strategies

COVID-19 patient data recorded in health care records, including routine demographic data, medical history, epidemiological exposure, comorbidities, symptoms, signs, laboratory results, CT scans, and clinical outcomes, were retrospectively analyzed. Interventional extracorporeal rescue therapies were performed according to pertinent ICU protocols. Upon ICU admission, we administered baseline therapy to all critically ill COVID-19 patients, including ventilation, antiviral treatment with Paxlovid, antibiotics, anticoagulation, and other supportive care in the ICU.

Statistical analysis

Categorical variables are presented as absolute numbers or percentages. Continuous parameters are expressed as the mean values ± SDs or median values with interquartile ranges (IQRs) depending on their distribution. Logistic regression was used for each studied parameter over the binary outcome (survival/death) in univariate analysis.

Results

The main parameters of high-risk patients with COVID-19 are summarized in Table 1. During the study period, 33 patients with COVID-19 and pneumonia were enrolled, with a mean age of 61.6 years. The percentage of males was 42.4%, and only 6.1% were smokers. Patients were divided into two groups, mild to moderate COVID-19 patients and patients with severe COVID-19, all of whom were high-risk patients. Of the 33 patients, 51.5% had comorbid hematological malignancies. Meanwhile, 21.1% of patients had comorbid solid tumors and 27.3% of patients had other comorbid conditions, such as chronic kidney disease and Parkinson’s disease (Table 1).

Other clinical characteristics of the patients, including outcome measures and symptoms, are also listed in Table 1. Four patients (12.1%) received MV. The median length of stay in the ICU was 11 days (interquartile range (IQR), 2–33 days).The median length of hospital stay was 17 days (IQR, 5–84 days). Thirty patients (90.9%) had caught. Twenty-seven (81.8%) patients had a fever. Sixteen patients (48.5%) had shortness of breath, and three (9.1%) patients had myalgia. The numbers and percentages of patients with mild to moderate COVID-19 and severe COVID-19 with the above characteristics are also shown in Table 1.

To investigate the effects of glucocorticoids (methylprednisolone) on high-risk patients with COVID-19, the definitions of high-risk patients for severe COVID-19 and mortality are listed in Table 2. These high-risk factors include age, living environment, COVID-19 vaccine, and underlying diseases. Patients who were older than 65 years, lived in nursing homes or living in long-term care facilities, had no vaccination or response to the COVID-19 vaccine, or had combined underlying diseases listed in Table 2 were defined as high-risk patients.^9,10

We used chest CT to guide the use of methylprednisolone. To provide precise guidelines, we summarized the characteristics of four stages of pneumonia lesions on chest CT, namely, the early, progressive, peak, and absorption stages, which are shown in Table 3. According to the WHO guidelines, glucocorticoids can be administered at the progression stage.³ However, all mild to moderate COVID-19 patients were given methylprednisolone at least at the early stage (Table 4). Unlike the WHO guideline recommended methylprednisolone dosage (40–80 mg), for mild to moderate COVID-19 patients, we used a low methylprednisolone dosage at first (median dose 26 mg, IQR 20–40 mg) and late, with a maximum median dose of 46 mg (IQR 20–120 mg). For patients with severe COVID-19, we initially used a median dosage of 41 mg (IQR 20–80 mg) and later a maximum median dose of 80 mg (IQR 60–120 mg). With respect to the duration of glucocorticoid use, the WHO guidelines state that the duration of glucocorticoid administration should be less than 10 days. In this study, the median duration of methylprednisolone administration for patients with mild to moderate COVID-19 was 12 days (IQR 2–33 days). The median duration of methylprednisolone administration for patients with severe COVID-19 was 25 days (IQR 7–43 days). There are no indications of glucocorticoid reduction according to the WHO guidelines. Here, we used CT images to guide methylprednisolone reduction. At the absorption stage, we reduced the methylprednisolone dosage to 18 mg (IQR 8–18 mg) for mild to moderate COVID-19 patients and 11 mg (IQR 7.5–15 mg) for patients with severe COVID-19. We also compared different methylprednisolone dosage regimens among different disease stages. The data in Figure 1 show that to achieve COVID-19 remission, a lower dose of methylprednisolone was needed for mild to moderate COVID-19 patients than for patients with severe COVID-19, and a lower dose of methylprednisolone was needed at early CT imaging stages than at progression CT imaging stages. Timely glucocorticoid reduction prevented the relapse of pneumonia. As shown in Table 5, with the exception of one patient with severe COVID-19 who died of pneumonia, all other high-risk patients with mild to moderate COVID-19 and patients with severe COVID-19 recovered from pneumonia, as indicated by negative SARS-CoV-2 amplification, pneumonia absorption in chest CT images, and the elimination of symptoms, including fever, cough, myalgia, and shortness of breath.

Table 3.

Definition of chest CT stages of COVID-19 pneumonia.

Pneumonia stage	Image features
Early/GGO	Multiple small spots in both lungs, pure GGO, unilateral, or bilateral subpleural distribution
Progression	Multiple lobes in both lungs with increased lesion density, and showed GGO mixed with crazy paving pattern and mesh shaped GGO mixed with solid shadow
Peak	GGO becomes solid, the fine mesh becomes coarse, and the mixed GGO and the solid shadow
Absorption	Solid crazy paving pattern gradually absorbed and improved, GGO narrowed, manifested as mixed GGO and messy cord shadow and rare pleural effusion

Table 4.

Methylprednisolone administration and reduction protocol.

Administration	WHO guideline	Our strategy
Administration	Severe COVID-19	COVID-19	Severe COVID-19
Chest CT	Progression stage	Early stage (GGO)	All stages
Methylprednisolone dose (IQR) (lowest–highest, mg)	40–80	29 (20–40)–46 (20–120)	41(20–80)–25 (7–43)
Dose reduction
Chest CT	NA	Absorption stage	Absorption stage
Maintenance dose (mg IQR)	NA	18 (8–80)	11 (7.5–15)

Figure 1.

Correlation between methylprednisolone dosage and initiation status. (a) Different doses of methylprednisolone were used to prevent pneumonia in patients with COVID-19 or with severe COVID-19. (b) Different doses of methylprednisolone were used to prevent pneumonia in patients with COVID-19 and severe COVID-19 at the early pneumonia stage by CT image (CT Early) or at the progression pneumonia stage by CT image (CT Progression). The data are expressed as mean + SD, **p < 0.01

Table 5.

Methylprednisolone reduces severe COVID-19 and mortality.

Parameters	COVID-19	Severe COVID-19
Clinical parameters
SARS-COV-2/PCR	100% negative	85.7% negative
Chest CT absorption, %	100%	85.7%
Mortality (n, death/total)	0/26	1/7
Symptoms
Caugh (n, %)	0, 0%	1, 14.3%
Fever > 38°C (n, %)	0, 0%	1, 14.3%
Myalgia (n, %)	0, 0%	1, 14.3%
Shortness of breath (n, %)	0, 0%	1, 14.3%

Discussion

This retrospective study revealed that, for high-risk patients with COVID-19, the administration of glucocorticoids at earlier ground-glass exudation stages and a slow reduction in the glucocorticoid dose are the two key points for preventing severe COVID-19 or mortality. Many reports have shown that glucocorticoid administration benefits patients with severe COVID-19. However, the intervention time window, dosage, and duration are controversial.¹¹ Three distinct stages of COVID-19 illness have been suggested by Siddiqi and Mehra¹²: early infection (stage I), pulmonary stage infection (stage II), and hyper inflammation stage infection (stage III). Siddiqi and Mehra suggested that at the hypoxia stage (stage IIA), anti-inflammatory therapies such as glucocorticoid injection may be given, as the pathogenesis is dominated by uncontrolled inflammation. Here, we used CT images to determine the glucocorticoid intervention time window and found that glucocorticoid administration at the pure GGO stage of chest CT benefits high-risk patients with COVID-19 (Table 4). A study by Fang et al.¹³ suggested that glucocorticoids may be administered early in the course of the disease, which is in line with our findings here. The results here provide clear and direct guidelines for glucocorticoid usage in high-risk patients with COVID-19. This study suggested that in addition to ICU patients with severe COVID-19, other subsets of patients in an earlier phase of the disease may also benefit from glucocorticoid therapy and possibly avoid ICU admission.

Although emerging reports have shown the benefits of steroids as life-saving drugs in hospitalized COVID-19 patients, the use of steroids in COVID-19 patients is confusing for many physicians. A meta-analysis by Thakur et al.¹⁴ revealed that the use of steroids in hospitalized COVID-19 patients is useful for reducing deaths. A subgroup analysis revealed that methylprednisolone significantly reduced the number of deaths of COVID-19 patients. Our retrospective study, which focused on the effects of methylprednisolone on high-risk patients with COVID-19, provided real-life evidence, and supported the conclusions of the meta-analysis.

Recently, many meta-analyses have been carried out to identify characters of COVID-19 or to find effective ways to treat it. For example, in a meta-analysis, Srivastava and Kumar¹⁵ reported that treatment with aspirin, a well-known anticoagulant, resulted in a lower likelihood of death in COVID-19 patients. Another meta-analysis by Song et al.¹⁶ revealed that treatment with baricitinib, an inhibitor of the Janus kinases JAK-1 and JAK-2 mediated excessive inflammatory response reduced mortality and MV requirements in patients with severe COVID-19. A meta-analysis by Vitalakumar¹⁷ revealed that neurological manifestations are significant in COVID-19 patients. A systematic review of meta-analyses by Garg et al.¹⁸ revealed a significant association of diabetes alone or its associated comorbidities with the deaths of COVID-19 patients. As shown in Table 2, diabetes and neurocognitive impairment are defined as high-risk factors for patients with COVID-19. These meta-analyses and systemic reviews provided helpful information for preventing severe COVID-19 or mortality. Notably, this retrospective study analyzed real-life data showing that early intervention with methylprednisolone, particularly during the early stages of lung involvement as observed in CT scans might be crucial in preventing the progression to severe COVID-19 in the population of high-risk patients with COVID-19.

In many clinical settings, glucocorticoids are used in patients with hypoxemia who are not at an early phase of the disease. As reported by Ana Fernández-Cruz,¹⁹ as many as 64% of patients fulfilled the ARDS criteria at the time of glucocorticoid administration, and certain rates of mortality were observed. In our series, glucocorticoid treatment at early CT image stages was beneficial in high-risk patients with moderate-to-severe COVID-19, although it did not reach statistical significance, possibly because of the small sample size. For patients with COVID-19 different high-risk criteria were used in different reports,^9,10 most of them containing the complications listed in Table 2. A review by Bartoletti et al.¹ suggested that there is still a lack of guidance for special COVID-19 populations such as those who are immunocompromised. Here data from the ECDC were referred to define risk factors and groups for severe COVID-19.⁸ Although the optimal stage for glucocorticoid treatment remains to be elucidated, this retrospective study revealed that for high-risk patients with COVID-19, glucocorticoid administration at the early GGO stage may be a therapeutic window to prevent progression to severe COVID-19 or mortality.

WHO guidelines recommend not using corticosteroids in patients with COVID-19 for more than 10 days.³ In the present study, patients received methylprednisolone treatment for a median of 12 days for mild to moderate COVID-19 patients and 25 days for patients with severe COVID-19 after the onset of symptoms. Our study suggested that a relatively longer duration may be necessary for preventing pneumonia recurrence. However, when chest CT shows an absorption stage, timely methylprednisolone reduction may protect patients from the side effects of methylprednisolone.

For the glucocorticoid dose, the WHO guidelines suggest a dosage ranging from 40 to 80 mg of methylprednisolone.³ However, the optimal glucocorticoid dose also needs clarification, especially for high-risk patients. Here, we initially used a median dose of 29 mg of methylprednisolone in pulses for patients with mild to moderate COVID-19 and an initial median dose of 41 mg of methylprednisolone in pulses for patients with severe COVID-19. This study revealed that early and low-dose glucocorticoid administration is beneficial for preventing severe COVID-19 or mortality in high-risk patients.

The vast majority of the patients in our hospital are immunocompromised and are not eligible for SARS-COV-2 vaccination. To test whether methylprednisolone is also effective in high-risk patients who are fully vaccinated, 18 fully vaccinated COVID-19 outpatients who meet the high-risk definition given in Table 2 were enrolled. When the general characteristics, methylprednisolone administration, and clinical parameters were compared between non-vaccinated high-risk COVID-19 patients in Table 1 (n = 26) with the vaccinated 18 high-risk COVID-19 outpatients, the data in Supplemental Table S1 showed that early [GGO] stage of chest CT) and low dose administration of methylprednisolone resulted in same response in non-vaccinated and vaccinated high-risk COVID-19. These results further indicate the importance of early glucocorticoid intervention.

Like many retrospective studies,²⁰ the present study included only high-risk patients and lacked a control group. So we did not calculate the samples size and just showed all the collected data in our hospital. As this retrospective study has a small sample size, a more diverse population, and as a single-center study, the results need external validation. In this retrospective study, methylprednisolone was given to high-risk patients with COVID-19 once lung involvement was observed in CT scans. Therefore, it remains unclear whether specific protocols or variations in treatment approaches yield different outcomes. Notably, we report an impact on in-hospital mortality. Table 5 shows that methylprednisolone administration at the early GGO CT image stage and with a low dose could decrease mortality compared with that reported in the literature²¹ and could increase oxygen saturation and the partial pressure of arterial oxygen (PaO₂)/percentage of inspired oxygen (FiO₂) ratio.

Conclusion

This retrospective study revealed that early intervention with methylprednisolone, particularly during the early stages of lung involvement, as observed via CT, might be crucial for preventing progression to severe COVID-19 and reducing mortality. This is a retrospective study that analyzes real-life data and we concluded that it is essential for early administration of methylprednisolone for high-risk populations with COVID-19.

Supplemental Material

sj-doc-1-smo-10.1177_20503121241276683 – Supplemental material for Effect of methylprednisolone in reducing severe COVID-19 and mortality in high-risk patients: A retrospective study

Supplemental material, sj-doc-1-smo-10.1177_20503121241276683 for Effect of methylprednisolone in reducing severe COVID-19 and mortality in high-risk patients: A retrospective study by Yan Xiao, Jinwei Wang, Kai Yang, Meiling Jiang, Jialin Luo, Kun Chen and Bo Zhang in SAGE Open Medicine

Footnotes

Author contributions

The authors confirm their contribution to the article as follows: Y.X., study conception and design; J.W. and K.Y., formal analysis, investigation, methodology; M.J. and J.L., data collection, methodology; K.C., project administration, data curation; B.Z., conceptualization, project administration, writing—review and editing. All authors reviewed the results and approved the final version of the article.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

Ethical approval for this study was obtained from the ethics committee of Beijing Gobroad Boren Hospital. The reference number is 2000040665.

Informed consent

Written informed consent was obtained from all subjects.

Trial registration

None.

ORCID iD

Yan Xiao

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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