To our knowledge, this study is the first to evaluate the effect of corticosteroids on the outcome of patients with severe/critical COVID-19 in China in the autumn/winter 2022 Omicron wave. In this study, most of the hospitalized patients with severe/critical COVID-19 in Chongqing were observed elderly, male gender and comorbidities. Older age, male gender, comorbidities, critically ill cases and longer days from the onset to admission were significantly more common in the corticosteroids group. The in-hospital mortality of hospitalized patients with severe/critical COVID-19 was 32.8%, and the 28-day mortality was 37.9%. Corticosteroids treatment did not reduce in-hospital and 28-day mortality of hospitalized patients with severe/critical COVID-19. Subgroup analysis yielded the same conclusion.
At the very beginning of the Omicron outbreak in Chongqing City, measures like suspension of public events, increasing lockdown areas and traffic restrictions were promptly taken by the government. Nevertheless, SARS-CoV-2 infection cases surged in a short time. In less than half a month, more than 8,000 new COVID-19 cases were reported in Chongqing, and the number was reported as more than 59,000 ten days later. According to the Chinese Center for Disease Control and Prevention, this wave of epidemic in China peaked in late December 2022 and then declined. By late January, the overall epidemic had dropped to a low level. From September 26, 2022, to January 23, 2023, a total of 18,906 indigenous cases of novel coronavirus genome were submitted nationwide, all of which were Omicron variants, 69 evolutionary branches, the main prevalent strains were BA.5.2 (70.8%) and BF.7 (23.4%) [20].
Although Omicron’s symptoms are relatively mild compared with Delta’s symptoms [21], in this study, the mortality rate of hospitalized severe/critical patients was 32.8%, and the 28-day mortality rate was 37.9% which was relatively higher. The reason may be that most study patients were observed as elderly, male and comorbidities. And the elderly have poorer basal lung function and immunity than younger people, resulting that an equivalent viral load will cause far more damage in this group than in younger people. In England, a large cohort study including 17.2 million adults indicated that male, greater age, deprivation and various other medical conditions were associated with COVID-19-related death [22]. The high death rates observed in study patients might also be partly attributed to the older population remaining largely unvaccinated and being first-time-infection. A study during the 2022 Hong Kong Omicron COVID-19 outbreak indicated that the risk for COVID-19–associated death among unvaccinated persons was higher than among recipients of 2–3 doses in the elderly (aged ≥ 60) [23]. Previous studies have also found that even if the vaccine is protective, it was still less effective in the elderly than in the young [24], possibly because of the poor basic lung function in the elderly [24].
In the corticosteroids group, a worse baseline respiratory situation was observed. Older age, male gender, comorbidities, critically ill cases and longer days from the onset to admission were significantly more common. This could be the reason why the length of hospital stay was longer in the corticosteroids group. Corticosteroids exposure increased with the severity of COVID-19 pneumonia. After adjusting by baseline characteristics, corticosteroids treatment was not associated with lower mortality than non-corticosteroids treatment.
Corticosteroids have broad, non-specific anti-inflammatory effects, which may affect mRNA transcription, thereby reducing the production of inflammatory mediators [25]. Therefore, the use of corticosteroids may reduce the complications caused by inflammatory storms. However, the immunosuppressed state of the respiratory epithelium may lead to delayed clearance of the virus, secondary infections and deterioration of disease. This is why the WHO recommends against the routine use of corticosteroids in the treatment of patients with severe COVID-19 in 2020[26].
Some studies showed that corticosteroids use was not associated with reduced mortality in patients with COVID-19[27, 28] and even led to an increased risk of death [29, 30]. Evidence for a low dose of methylprednisolone has been limited to date. A large, double-blind, randomized controlled trial allocated (1:1 ratio) patients randomly to receive either intravenous methylprednisolone (0.5 mg/kg) or placebo (saline solution) [31]. And this study suggested that a short course of methylprednisolone in hospitalized patients with COVID-19 did not reduce mortality in the overall population which was consistent with our study. The same conclusion was also obtained in a retrospective study that included 102 adult COVID-19 patients analyzing the clinical effect and prognosis of critical COVID-19 patients treated with low doses and short courses of methylprednisolone (0.75–1.5 mg/kg/d, usually for less than 14 d) [30]. In our study, most of the patients (87.9%) in the corticosteroids group were treated with low-dose methylprednisolone.
In 2020, dexamethasone was the first drug to be identified which was able to reduce mortality in severe or critically ill patients with COVID-19 who received oxygen therapy [4]. Subsequent research found that methylprednisolone could be used for treating severe COVID-19[32–35]. However, the application and dose of methylprednisolone are still controversial [11, 30, 36–38]. The efficacy and safety of high versus low doses of corticosteroids for the treatment of patients with COVID-19 have shown mixed outcomes in controlled trials and observational studies [6, 38–40]. There were still a lot of research suggesting that low-dose corticosteroids (<15 mg/d dexamethasone,<400 mg/d hydrocortisone, and<1 mg/kg/d methylprednisolone) are beneficial in the treatment of patients with severe COVID-19 pneumonia[28, 41] or even reduced mortality in patients with COVID-19 pneumonia[4, 8, 42].
Currently, in China, low-dose and a short course of corticosteroids are recommended in severe and critical cases of COVID-19[15, 16]. Almost all of the study patients in this study had corticosteroid treatment for less than 10 days which was similar to Jeronimo’s study [31]. In 2021, a systematic review and meta-analysis published in Intensive Care Med found that patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course [43]. As is known to all, different time and duration of corticosteroids administration might have affected the observed outcome. And continuous administration of corticosteroids may suppress the immune system and slow down viral clearance [44]. Long-term corticosteroids use can also lead to elevated blood glucose, ischemic necrosis of the femoral head, osteoporosis, secondary fungal infections, and glucocorticoid-induced psychosis.
When viral replication is active in vivo, the human immune system can provide beneficial protection by killing the virus. But in some cases, the human immune system can also cause harmful damage by infinitely activating local inflammatory reactions [45]. The choice of corticosteroids is to inhibit the body's immune system, so the decision requires full consideration. It is necessary to assess whether the virus is replicating and whether there is secondary damage caused by inflammation. Theoretically, patients with no active virus in vivo but a significant inflammatory response are most appropriate to receive corticosteroids. And the meantime effective antiviral therapy is also important.
This study has some limitations. First, it was a retrospective study in six Chongqing centers. The relatively small sample size may lead to an underestimation of the efficacy of corticosteroids. Second, this study did not analyze the data about income and vaccination history for SARS-CoV-2 because the data were hard to get retrospectively. Third, we had no chance to evaluate serious adverse events of corticosteroids in our study although the probability of occurrence is small.
This is the first report evaluating the efficacy of low doses of corticosteroids among hospitalized patients with severe/critical COVID-19 in China autumn/winter 2022 Omicron wave. We ensured strict quality control, including data collection, internal quality control, and external supervision. All information regarding cases and controls was extracted retrospectively from the medical records of patients by trained physicians.