key: cord-1007825-es54ajmv
authors: Zhan, Yuan; Shang, Jin; Gu, Yiya; Huang, Qian; Xie, Jungang
title: Efficacy of corticosteroid in patients with COVID‐19: a multi‐center retrospective study and meta‐analysis
date: 2021-03-05
journal: J Med Virol
DOI: 10.1002/jmv.26914
sha: 06da48f69b05be6bb28fade79f5673f3f04d1a45
doc_id: 1007825
cord_uid: es54ajmv

PURPOSE: To evaluate the efficacy of corticosteroids on COVID‐19 patients with different levels of disease severity. METHODS: In our multicenter study, 543 patients with confirmed COVID‐19 were classified as Non‐severe group and Severe group, and then were compared respectively for all‐cause mortality and length of hospital stay between those who received corticosteroids and not. By searching in PubMed, Web of Science, Embase and CNKI, we identified 13 retrospective studies and 6 random control trials eligible for criteria of inclusion, and conducted comprehensive meta‐analyses assessing the impacts of corticosteroids on mortality, length of stay, duration of RNA clearance and duration of fever. RESULTS: Our multicenter study demonstrated that low‐dose corticosteroids can reduce mortality in the multivariable Cox regression analysis for severe patients(p=0.03), while presented no influence in univariable analysis for non‐severe patients(p=0.14). From multivariable analyses, patients with corticosteroids in non‐severe group had longer duration of hospitalization(p=0.003), but did not in severe group(p=0.18). Moreover, for severe patients, corticosteroids can evidently shorten duration of fever. The same results were summarized in the meta‐analyses supplemented with the result that corticosteroids delayed viral clearing in non‐severe patients. CONCLUSION: Corticosteroids should be considered based on patient's condition. For patients with non‐severe COVID‐19, corticosteroid was not recommended as a routine therapeutic initiative as that presented prolonged duration of hospitalization and delayed viral clearing, as well as no positive impact on prognosis. While low‐dose corticosteroids may benefit patients with severe COVID‐19 for it can manifestly lower risk of death and improve the clinical status to some extent. This article is protected by copyright. All rights reserved.

In December 2019, the first pneumonia case caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), now known as coronavirus disease 2019 (COVID- 19) , was identified in Wuhan, Hubei Province, China 1 . SARS-CoV-2 infection was then quickly spread globally 2-4 . Evidence shows that the person-to-person transmission is the main cause of the large-scale outbreak of COVID-19 5 . As of Sep 20, 2020 , there has been more than 30 million confirmed cases worldwide and nearly one million deaths. This article is protected by copyright. All rights reserved.

Previous studies had reported various therapeutic initiatives and effect assessment related to COVID-19, including antiviral, immunotherapy, corticosteroid therapy and other symptomatic supportive treatments, but there are still no specific drugs for treatment and control. Thereinto, corticosteroid was widely used in patients with COVID-19 pneumonia, while its efficacy remains controversial. Given the experience and lessons of severe acute respiratory syndrome (SARS) treatment, improper use of systemic corticosteroids can increase the risk of secondary infection, osteonecrosis of the femoral head, hypokalemia, etc 6-8 . Meanwhile, several observational studies in the early stage of COVID-19 outbreak suggested that corticosteroid treatment may increase the mortality to some extent 9,10 . Tang et al. 11 called for caution in the use of corticosteroids for COVID-19 and did not recommend this as a routine treatment.

To date, three meta-analysis articles summarized the effects of corticosteroid therapy mainly including studies on SARS and MERS, as well as several early-stage observational studies of COVID-19, and suggested that employment of corticosteroids cannot improve survival or reduce length of hospital stay, but spark some adverse effects [12] [13] [14] . Due to the heterogeneity of disease among SARS, MERS and COVID-19, and non-specificity of the study cohorts for the literatures of COVID-19 included in the meta-analysis, the reliability of the results needs further verification.

Afterwards, multiple cohort studies and randomized controlled trials primarily to compare the mortality of COVID patients who did receive or not receive corticosteroid emerged within a short period. In early September, a prospective meta-analysis of clinical trials of critically ill patients with COVID-19 reported that administration of systematic corticosteroid was associated with lower 28-day all-cause mortality, which clearly demonstrated the benefit of corticosteroid therapy 15 . However, there is currently no high-quality meta-analysis to systematically compare the Accepted Article

All data collected from the hospital's electronic medical record system of every hospital were as follow: demographic characteristics (Age and Gender), medical history of chronic disease (Hypertension, diabetes, Chronic Respiratory, Liver and Renal disease), sign and symptoms (Fever, Cough, Shortness of breath, Temperature, Respiratory rate and Heart rate), laboratory findings on admission (PaO 2 , WBC, CRP, Alanine aminotransferase, Bilirubin, Alkaline phosphatase, Creatinine and Lactate dehydrogenase) and treatment information (Antiviral, Antibacterial, Immunotherapy, Oxygen delivery and Corticosteroid therapy), as well as clinical outcomes (Mortality and Length of hospital stay). These data were then collated, analyzed and interpreted by researchers from the Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology.

The main exposure was the employment of corticosteroid therapy between Severe/Corticosteroid cohort and Non-severe/Corticosteroid cohort. We explicitly recorded the type of corticosteroid, daily dosage and duration of treatment. The primary outcomes included mortality and length of hospital stay. Fever was defined as axillary temperature exceeding 37.3 °C.

The date of disease onset was marked by the first appearance of fever (either reported by the patient or confirmed by measurement), cough, or other related clinical symptoms with or without abnormal imaging results.

Continuous variables were expressed as median (IQR) as they were not distributed normally, and categorical variables were expressed as number (%). The Mann-Whitney U test was employed

year, study design and research country); (2) patient characteristics (total number of participants, severity of disease, gender and age); (3) exposure or intervention details (type of corticosteroid, dosage and duration of therapy); and (4) outcomes (mortality, length of hospital stay, duration of RNA clearance and duration of fever). To assess the risk of bias, two authors (Y Zhan and Y Gu) used the Newcastle-Ottawa Scale (NOS) for the retrospective studies 16 and Jadad score for the RCTs 17 . The NOS scores were achieved by evaluating selection, comparability and outcome categories with a maximum of 9. While the Jadad scores were obtained by evaluating three domains of randomization, blinding, and dropouts/withdrawals with a maximum of 5. We considered the study with a NOS score≥6 or Jadad score≥3 as high quality.

The mete-analysis was conducted using Review Manager 5.3 (The Cochrane Collaboration).

We pooled eligible data and described the continuous data by mean difference (MD) with 95% confidence interval (CI), while the dichotomous data by risk ratio (RR) with 95% CI. Studies with an I² statistic<50% were considered to have no heterogeneity, where the fixed-effects model was chosen. While those with an I² statistic≥50% are considered to have heterogeneity, where the random-effects model was chosen. A sensitivity analysis was conducted by detecting the stability for the composite outcome of the remaining studies when excluding one study at a time. The funnel plots were used to assess the potential publication bias. P<0.05 (two-sided) was considered statistically significant. The values of daily dosage were not different significantly(p=0.52) in patients who received corticosteroid between NC and SC cohorts, and both values of median dosage were 40 regarded as a low-dose administration. While the median treatment period in NC was 6 days(4~9) shorter evidently than that in SC(8 days(5~10)) with p =0.003.

For mortality, there was no difference between NC and NN as was shown in Table1, while it's different significantly between SC and SN(p=0.02). To explore the efficacy of corticosteroid This article is protected by copyright. All rights reserved.

therapy on mortality for Severe group, some variables different significantly in Table1(p<0.05) were included into univariable Cox regression to screen for potential confounding factors, including respiratory rate (RR), arterial partial pressure of oxygen (PaO 2 ), lymphocyte count, c-reactive protein (CRP), lactate dehydrogenase, antibacterial and immunotherapy. We chose as the final inclusion into multivariable Cox regression the factors that was significantly different in univariable Cox regression analysis and potentially affected the prognosis, namely CRP, lactate dehydrogenase, immunotherapy and corticosteroid therapy. Result of multivariable Cox regression analysis suggested that administration of corticosteroids could clearly reduce the mortality for patients in Severe group (Fig 1A) .

In the same way above, we performed Cox regression analyses regarding the influence of corticosteroids on the length of hospital stay for non-severe patients and severe patients respectively. Eventually, the variables included in the multivariable Cox regression analysis for Non-severe group were antibacterial and corticosteroid therapy, while CRP, PaO 2 , lactate dehydrogenase, immunotherapy, antibacterial and corticosteroid therapy for Severe group.

Surprisingly, corticosteroid therapy can obviously prolong the length of hospital stay for Non-severe group (Fig 1B) , but not for Severe group (Fig 1C) .

Combined with the result of meta-analysis (Fig 5) , we purposefully collected the temperature values of patients in Severe group on admission, on day 3, on day 5 and on discharge/death. As indicated in Fig 1D, the mean temperature on admission in SC cohort was 37.9 ℃ slightly higher than that of 37.6 ℃ in SN cohort without any difference(p=0.26). But on day 3, patients who received corticosteroids restored rapidly to a mean temperature of 36.7℃, and there was significant Accepted Article associated with lower mortality (RR=0.88, 95% CI: 0.81 to 0.95, I 2 =49%) and the sensitivity analysis was stable.

To assess the influence of corticosteroids on length of hospital stay, 12 studies with 1300 patients were included in the meta-analysis, of which 10 were retrospective studies and 2 were RCTs (Fig 3) . Overall, corticosteroids may prolong the duration of hospitalization (MD=2.48 days, 95% CI: 0.51 to 4.45, I 2 =82%). Subgroup analyses of retrospective studies suggested that corticosteroids can significantly increase the length of stay in Non-severe patients (MD=4.61 days, 95% CI: 2.75 to 6.46, I 2 =63%) and sensitivity analysis was stable, but not in Severe patients (MD=-1.39 days, 95% CI: -4.38 to 1.60, I 2 =0%). There was also no impact for subgroup analysis of RCTs (MD=-2.36 days, 95% CI: -8.90 to 4.18, I 2 =90%).

To investigate the impact of corticosteroids on duration of RNA clearance, only 11 retrospective studies with 627 subjects were analyzed (Fig 4) . Pooled data indicated that corticosteroids cannot delay the RNA clearing (MD=1.56 days, 95% CI: -0.01 to 3.14, I 2 =56%).

But the subgroup analysis of Non-severe patients demonstrated that corticosteroid therapy was associated with prolonged duration of RNA clearance (MD=2.03 days, 95% CI: 0.30 to 3.77, I 2 =57%) and sensitivity analysis was stable.

To evaluate the influence of corticosteroids on duration of fever, 5 retrospective studies with 378 patients were included in the meta-analysis, where there were 300 non-severe patients and 78 severe patients (Fig 5) . The overall result showed corticosteroid therapy had no distinct impact on

Hasan et al. classified the disease process of COVID-19 as three stages, namely early infection, lung progression and hyperinflammation phase 39 . In the stage of early infection, patients often presented with some mild or non-specific symptoms, such as fever and cough. He proposed that treatment at this stage was primarily targeted toward symptomatic relief and avoided the use of corticosteroids. Surprisingly, what resembled to Hasan's proposal was that corticosteroids were not recommended for patients with non-severe COVID-19 as that cannot significantly reduce mortality or duration of fever, and even may increase the duration of hospital stay and delay viral RNA clearing, which were concluded from our meta-analysis and further validated in our multi-centered study. A preliminary clinical trial 31 reported that the use of dexamethasone was not associated with 28-day mortality in patients who received no oxygen therapy, which provided a robust evidence demonstrating the unnecessity of corticosteroids among non-severe COVID-19

patients. In addition, consistent with studies on SARS and MERS 40,41 , systematic corticosteroids in COVID-19 may also lead a delayed viral RNA clearing and a prolonged length of hospital stay. As indicated by Hasan 39 , stages of early infection and lung phase were considered as viral response phase where virus performed rapid replication, while early initiation of corticosteroids at this phase resulted in delayed viral clearance (thus a higher subsequent plasma viral load) 40 . Although it's reported in early-stage observational studies that the prolonged duration of hospitalization was primarily associated with the more severe baseline characteristics in patients who received corticosteroid therapy, we considered the delayed role of corticosteroids on viral clearing as main cause for prolonged duration of hospitalization on account of the relatively balanced baseline characteristics between NC and NN cohorts in our multi-centered study. Consequently, for patients with non-severe COVID-19, corticosteroid therapy presented no manifest improvement in survival,

and delayed viral clearing and increase length of hospital stay instead.

In severe COVID-19 pneumonia, patients' symptoms worsen rapidly and were considered in hyperinflammation phase where proper corticosteroid was recommended to suppress the cytokine storm 39,42 . Corticosteroid is a classical immunosuppressive drug that helps in delaying or halting the progress of pneumonia and has been effective for the treatment of ARDS 43, 44 , and meanwhile serves as an anti-inflammatory agent that reduces systemic inflammation, decreases exudation into the lung tissue, promotes the absorption of inflammation, and prevents alveolar damage 45 . These effects of corticosteroids may improve the prognosis of severe COVID-19 patient to some extent.

In the meta-analysis of RCTs regarding mortality, the risk ratio was 0.88 with 95% confidence interval from 0.81 to 0.95 in favor of corticosteroid therapy. Given that subjects in RCTs substantially consisted of patients with severe COVID-19, the administration of corticosteroids in severe-type patients should be adopted properly, which was also suggested in a prospective meta-analysis of clinical trials 15 . Moreover, we also conducted Cox regression analysis to further confirm the beneficial role of corticosteroids in survival of severe patients. As indicated, due to the host' susceptibility to hyperinflammation in severe-type patients, corticosteroids functioned as the anti-inflammatory agent with the capability to suppress inflammation and lower body temperature rapidly in patients at this stage 39 . This effect was also demonstrated in the subgroup analysis of retrospective studies (severe) and multicenter study. In addition to a shorter duration of fever, a faster improvement of SpO 2 was found in cases of severe SARS-CoV-2 pneumonia treated with low-dose, short-term methylprednisolone, which was possibly associated with the effectiveness of corticosteroid on hypoxemia 44, 46 . To summarize briefly, corticosteroid therapy can help in either reducing the mortality or improving the clinical status in patients with severe COVID-19.

Furthermore, previous meta-analysis demonstrated that corticosteroids may increase length of hospital stay 12,13 . In contrast, a recently published clinical trial 32 suggested that corticosteroids decreased length of stay evidently. While the length of stay was not significantly prolonged in severe-type patients who received low-dose corticosteroids either in multivariable Cox regression or in our meta-analysis. Interestingly, although the duration of RNA clearing was not collected in our multicentered study, the result of subgroup meta-analysis suggested that corticosteroids had no significant impact on duration of RNA clearance in patients with severe COVID-19, which may be associated with patients at this stage primarily characterized with host hyperinflammation activity and having completed the stage of virus replication. It can be speculated that the clearing of viral RNA may be closely related to the length of the patient's hospital stay. Besides, we also considered the severity of disease and some unknown reasons possibly masking the role of corticosteroids.

More large-scale and rigorously designed random control trials are required to further elucidate the specific impact of corticosteroid on length of hospital stay and virus clearing in the future.

There remain some limitations in this study. First of all, the exact time of viral RNA shedding was untested timely and recorded owing to the overwhelming medical pressure and restrained medical resources then. What's more, the dynamic change of temperatures for non-severe patients was not collected with the values lacking too much to statistically analyze. Finally, the literature search was not performed in each database on account of the inaccessibility.

In conclusion, the therapeutic response to corticosteroids differed in patients with different severity of disease. For patients with non-severe COVID-19, corticosteroids were not recommended as a routine therapeutic initiative as that presented the prolonged duration of hospitalization and delayed viral RNA clearing, as well as no impact on mortality and duration of Accepted Article

The data that support the findings of this study are available from the corresponding author upon reasonable request. RR, Respiratory rate. HR, Heart rate. PaO 2, Arterial partial pressure of oxygen. CRP, C-reactive protein. 

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