Introduction
Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of 2019 novel coronavirus disease (COVID-19) [
1]. To date, SARS-CoV-2 has spread to over 200 countries and areas worldwide, and the number of confirmed cases and death cases has been quickly growing. As of July 4, 2020, there have been 10,922,324 confirmed cases and 523,011 deaths globally [
2]. The disease spectrum of COVID-19 ranges from mild self-limiting disease to severe disease necessitating hospitalization and intensive care unit (ICU) [
3]. At present, there is an absence of any proven effective antiviral therapy.
The main pathological changes of SARS-CoV-2 infection are characterized by ongoing lung inflammation, exudative pulmonary edema, which may be responsive to corticosteroids therapy [
4]. Corticosteroids may diminish the inflammatory response, a major factor for lung damage and acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection. Use of corticosteroids-based therapy to reduce inflammatory-induced lung injury has been described for patients with severe COVID-19 [
1,
5], similar to the use of corticosteroids to treat severe acute respiratory syndrome (SARS) in 2003 [
6]. Russell et al. [
7] reported that there appeared to be some evidence that corticosteroids may be beneficial if utilized in the early acute phase of SARS-CoV-2 infection; however, conflicting evidence from the World Health Organization (WHO) surrounding corticosteroids use in SARS-CoV-2 infection means this evidence is not conclusive. Han et al. [
8] reported that the long-term use of corticosteroids might cause atypical infections, a long incubation period, and extra transmission of COVID-19. Tang et al. [
9] call for caution in the use of corticosteroids for COVID-19 and do not recommend corticosteroids as a routine treatment.
For non-severe COVID-19 pneumonia, should corticosteroids be forbidden? What would be the advantages and disadvantages of corticosteroids therapy in non-severe COVID-19 pneumonia? In the early stages of the outbreak of COVID-19, early, low-dose, and short-term corticosteroids were used in partial non-severe cases with COVID-19 pneumonia in our hospital. In this retrospective study, we compared the clinical outcomes of patients with non-severe COVID-19 pneumonia treated with and without corticosteroids.
Discussion
Corticosteroids therapy of patients with COVID-19 is common in clinical practice, but the efficacy remains a major controversy. Some patients with COVID-19 exhibit biphasic disease evolution with a mild presentation followed by a secondary respiratory deterioration. Theoretically, early corticosteroids therapy might reduce inflammatory response, and prevented the progression of COVID-19. However, many questions regarding the use of corticosteroids in the treatment of COVID-19 remain unanswered, including the efficacy, the appropriate timing of initiation, and the dose. In this study, we evaluated the efficacy of early, low-dose, and short-term corticosteroids therapy in adults hospitalized with non-severe COVID-19 pneumonia. Our results indicated that early, low-dose, and short-term corticosteroids therapy was associated with worse clinical outcomes in the treatment of patients with non-severe COVID-19 pneumonia.
Generally, corticosteroids are considered to induce a decrease in body temperature and help alleviate the poisoning symptoms of virus infection including fever, headache, fatigue, myalgia, and so on. However, in this study, compared to the non-corticosteroids group, there was a prolonged duration of fever (median 5 vs 3 days,
p < 0.001) in the corticosteroids group. Zha et al. [
15] also found that there was a prolonged duration of symptoms (median 8 vs 6.5 days) in the corticosteroids group compared to the non-corticosteroids group. Yuan et al. [
16] found that there were no statistically significant differences in duration of fever (9.5 vs 10.2 days,
p = 0.28) between patients who received and those who did not receive corticosteroids treatment. On the basis of these studies, we suggested that corticosteroids may not be helpful in shortening the duration of fever. Although the temperature decreased temporarily, it increased again when corticosteroids wear off. The prolonged duration of fever could be attributed to delayed SARS-CoV-2 clearance due to the immunosuppressive effect of corticosteroids.
In this study, compared to the non-corticosteroids group, there was a prolonged virus clearance time (median 18 vs 11 days,
p < 0.001) in the corticosteroids group. The results were consistent with previous studies. Ling et al. [
17] reported that the duration of SARS-CoV-2 RNA in the corticosteroids group was longer than that in the non-corticosteroids group (15 vs 8.0 days,
p = 0.013). Ma et al. [
18] proposed that SARS-CoV-2 RNA clearance would be delayed because of the immunosuppressive effect of higher dose of glucocorticoids. Li et al. [
19] included 10 cohort studies and one randomized clinical trial involving 5249 subjects, and found that corticosteroids use in subjects with SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV infections delayed virus clearing. A retrospective study by Yuan et al. [
16] also found that compared to the non-corticosteroids group, corticosteroids group had longer duration of SARS-CoV-2 shedding (20.3 vs 19.4 days,
p = 0.669).
In this study, more patients in the corticosteroids group developed severe disease (12.7% vs 1.8%,
p = 0.028) than did in the non-corticosteroids group. The results were consistent with some previous studies. Xu et al., reported a patient with COVID-19 treated with methylprednisolone since day 8 of the disease course. However, his situation worsened and developed respiratory failure and died on day 14 [
4]. A meta-analysis included 5270 patients from 15 studies, and found that corticosteroids treatment was associated with higher mortality (RR = 2.11, 95% CI = 1.13–3.94,
p = 0.019), longer length of stay (weighted mean difference [WMD] = 6.31, 95% CI = 5.26–7.37,
p < 0.001), and a higher rate of bacterial infection (RR = 2.08, 95% CI = 1.54–2.81,
p < 0.001) in patients with COVID-19 [
20]. Yuan et al. [
16] also found that compared to the non-corticosteroids group, the corticosteroids group had more patients with non-severe COVID-19 pneumonia who developed severe disease (11.4% vs 2.9%,
p = 0.353). According to the aforementioned studies, corticosteroids might have a negative effect on lung injury recovery in non-severe COVID-19 pneumonia.
Corticosteroids therapy of severe patients with COVID-19 has been widely studied. Goursaud et al. [
21] reported that some selected patients with severe COVID-19 would benefit from wise and timely use of corticosteroids. Yang and Lipes [
22] described a case series of 15 patients with COVID-19 admitted to ICU who received corticosteroids in the context of cytokine release syndrome, and found a significant clinical and biochemical association between corticosteroids therapy and improved surrogate outcomes. A meta-analysis found that corticosteroids therapy may reduce mortality for patients with COVID-19 and ARDS (RR 0.72, 95% CI 0.55–0.93, mean difference 17.3% lower) [
23]. Another meta-analysis also found that methylprednisolone could lower the mortality rate in more severe forms of this condition, such as in ARDS [
24].
The RECOVERY Collaborative Group performed a controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with COVID-19, and randomly assigned patients to receive dexamethasone orally or intravenously (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone [
25]. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%, RR 0.64, 95% CI 0.51–0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%, RR 0.82, 95% CI 0.72–0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs 14.0%, RR 1.19, 95% CI 0.91–1.55) [
25]. In this study, our results indicate that the use of corticosteroids increased the risk of COVID-19 progression to severe disease, increased the use of antibiotics, and prolonged duration of fever, virus clearance time, and length of hospital stay in non-severe COVID-19 pneumonia. Our results were not contradictory with the results of the RECOVERY study, which showed that the use of dexamethasone resulted in lower 28-day mortality among patients with COVID-19 who were receiving either invasive mechanical ventilation or oxygen alone (severe cases mainly) but not among those receiving no respiratory support (non-severe cases mainly).
This study has several limitations. First, the study is retrospective. The uses of corticosteroids were decided by joint discussion of five experts from the Shanghai Medical Expert Group for the Treatment of COVID-19, on the basis of the demographics, laboratory parameters, and CT scans of patients. As a tentative therapy, considering the side effect and dubious curative effect, corticosteroids were used selectively for patients with more risk factors for a worse evolution of COVID-19 (or even more severe) than control patients. In order to reduce the biases and weaknesses caused by selective deviation, propensity score was used to balance the differences between the corticosteroids group and control group. However, propensity score is limited by adjusting for observed variables only; it cannot account for residual confounding of many of variables. Therefore, our results need confirmation in a prospective randomized clinical trial. Second, the dose and duration are critical to evaluate the efficacy of corticosteroids. In this study, the actual dose (20 mg/day or 40 mg/day) and duration (3 days or 5 days) of corticosteroids are absolute rather than calculation by milligrams per kilo. The dose and duration of corticosteroids were not randomized, but decided by joint discussions of five experts from the Shanghai Medical Expert Group for the Treatment of COVID-19. The selective biases in dose and duration of corticosteroids might affect the efficacy of corticosteroids in non-severe COVID-19 pneumonia. Third, no children were enrolled in this study because children with COVID-19 were hospitalized at another designated hospital in Shanghai.
Acknowledgements
We thank the doctors (Shui-Bao Xu, Yi-Xiao Lin, Feng Li, Tao Li, Zhiping Qian, Jun Chen, Bi-Jie Hu, Sheng Wang, En-Qiang Mao, Lei Zhu, Wen-Hong Zhang, Yinzhong Shen) for their efforts in the diagnosis and treatment of patients.