Following the release of the sixth edition treatment guideline for COVID-19 by National Health Commission of China, the systematic corticosteroids treatment was recommended as adjuvant therapy, and around 18-44.9% infected patients received this therapy.3,4 It raises a hot debate about whether patients could benefit from this therapy, as well as the timing and dosage of corticosteroid. Based on our previous study, we observed that a reverse of deterioration in 80% of seriously ill COVID-19 patients, defined by National Health Commission of China guideline, after a low-dose (80mg/d) corticosteroid treatment in combined with immunoglobulin (data not shown, manuscript submitted).2 In this study, we focused on the other 20% of patients who failed to control the progression after initial low-dose therapy. We proposed that a moderate-dose corticosteroid (160mg/d) for short-term in combined with immunoglobulin for these patients. Our results showed that this therapy could effectively reverse the disease progression in 90% (9/10) patients with worsened condition. The key indicators improved after treatment also has been identified through retrospectively analyzing the clinical data.
Corticosteroid is a double-edged sword in the treatment of viral pneumonias, which plays advantages only when administrated properly and precisely. Conventionally, the corticosteroid was the last life-saver choice, which was only recommended in the fatal-stage of pneumonia. In controlling such critical inflammation storm, we have no choice but to use high-dose corticosteroid. Through previous lessons in combating pneumonias including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and H1N1, high dose of corticosteroid administration was identified with no benefit in reducing mortality rate, but a higher risk of side-effects including immunosuppression and opportunistic infections.5-7 Some scholars suggested a low or moderate dose therapy but late until the phase of acute respiratory distress syndrome (ARDS).8 However, it is hard to imagine that suppression of furious inflammatory storm could be achieved with low dose corticosteroid. In this study, we advanced our therapy with a novel opinion, namely, to earlier our corticosteroid treatment time window. Low-dose corticosteroid therapy should be under consideration when clinical data indicates the progression of COVID-19.
First, the relatively mild inflammatory response in the early stage of COVID-19 pneumonia allows low dose of corticosteroid to control the progression of inflammation effectively. Studies with low or moderate dosage therapy showed no significant impact in mortality rate for H7N9 cases, and low dose even benefits the mortality rate in severe H1N1-illness, which supports the safety of low-to-moderate corticosteroid in viral pneumonia.9,10 In addition, we strongly recommend a combined use of immunoglobulin with corticosteroid, which could strengthen patients’ immune response to avoid excessive viral spreading and win us a relative safer and longer timeframe for corticosteroid therapy. And the combination use of immunoglobulin and corticosteroid in SARS treatment revealed better hazard ratio of mortality of 0.41 in comparison with cases with only corticosteroid.11 Thus, our initial low-dose treatment is administrated for 7-14 days, longer than the time recommended in the official guideline.2 During the treatment, the administration dose is adjusted according to the alleviation or progression of disease. Among the total COVID-19 patients admitted in our center, around 80% of the seriously ill cases had significantly improved after initial early low-dose of corticosteroid plus immunoglobulin (unpublished), an exciting data that have not been reported in any other center.
On the other hand, around 20% of patients continue progressing to more serious condition after initial low-dose therapy. For those patients, we choose a short-term moderate corticosteroid therapy plus immunoglobulin. The moderate dose was sufficient to perform well in controlling inflammatory response before entering more worsened condition including ARDS. We also doubled the dose of immunoglobulin to compensate for the possible immune suppression from moderate therapy. Meanwhile, we kept close attention to clinical indicators during the treatment. When improvements in crucial indicators were witnessed, the dose would be adjusted to initial dose immediately, which could maximize the effectiveness of controlling excessive inflammation response and minimize the possible side effect from moderate dose. Zhou et al. first explored the possible of moderate-dose corticosteroid (median hydrocortisone- equivalent dose of 400.0 mg/d, an average of 9.5 d) in ICU patients with COVID-19 infection. They observed the ICU mortality rate up to 46.7% (7/15), indicating the corticosteroids might not improve ICU mortality for critical ill patients.8 For the different results in effectiveness between our and Zhou’s study, it is reasonable for us to doubt that the delayed timing of administration, namely the possible delay in low-dose therapy, and a lack of immunoglobulin for protecting immune function might covered the benefits of this therapy in some cases.
Another key issue is how to judge the progression in illness condition for COVID-19, subsequently administrate corticosteroid at an earlier stage. The recommended guideline demonstrated the importance of lowered oxygenation saturation, progresses in chest radiography, and laboratory abnormalities reflecting furious inflammatory response in determining the use of low-dose corticosteroids. With cases in our center, we comprehensively considered the clinical indicators mentioned above for initial use and dose adjustment. By analyzing the changes before and after our treatment strategy for these ten patients, we highlighted the value of oxygenation index reduction, lung lesion progression in CT scan, and lymphopenia. Consistent with our findings, these indicators also showed strong correlation with disease progression in COVID-19 and SARS.4,11,12
The limitation of our study also needs to be addressed. First, a retrospective study instead of randomized controlled trail performed due to ethical considerations, which lowers the level of evidence. Besides, the study was limited by small sample size, with only ten confirmed COVID-19 patients in our center, with a failure of achieving improvement after initial low-dose corticosteroid therapy plus immunoglobulin. Finally, the clinical data was collected from Jan 17th to Feb 27th, which still requires long-term follow-up for the clinical outcome for all patients.
In conclusion, the short-term moderate-dose corticosteroid in combined with immunoglobulin could take good control of inflammation response, stabilize the immune function, and minimize the side-effect from corticosteroid. Our treatment strategy effectively reversed the progression for those serious COVID-19 patients, which draws our attention to reevaluate the value of low to moderate dose corticosteroid therapy in viral pneumonia. In our battle against COVID-19 outbreak, an offensive rather than defensive position in corticosteroid therapy might buy us time before specific antiviral medicines and vaccines emerge.