Short-term Moderate-dose Corticosteroid Plus Immunoglobulin Effectively Reverses Covid-19 Patients Who Have Failed Low-dose Therapy

Background: The coronavirus disease-19 (COVID-19) has spread globally with more than 6,750,000 people infected, and nearly 400,000 patients died. Currently, we are in an urgent need for effective treatment strategy to control the clinical deterioration of COVID-19 patients. Methods: The clinical data of 10 COVID-19 patients receiving short-term moderate-dose corticosteroid (160mg/d) plus immunoglobulin (20g/d) were studied in the North Yard of The First Hospital of Changsha, Hunan from January 17 th to February 27 th , 2020. Epidemiological, clinical, laboratory, radiological ndings were analyzed. Results: After treatment with combination of low-dose corticosteroid (40-80mg/d) and immunoglobulin (10g/d), patients’ lymphocyte count (0.88±0.34 vs 0.59±0.18, P<0.05), oxygenation index including SPO 2 (94.90±2.51 vs 90.50±5.91, P<0.05) and PaO 2 /FiO 2 (321.36±136.91 vs 129.30±64.97, P<0.05) were signicantly lower than pre-treatment, and CT showed that the pulmonary lesion deteriorated in all patients. While after treatment of short-term moderate-dose corticosteroid plus immunoglobulin, patients’ APACHE (cid:0) score (9.10±6.15 vs 5.50±9.01, P<0.05), body temperature (37.59±1.16 vs 36.46±0.25, P<0.05), lymphocyte count (0.59±0.18 vs 1.36±0.51, P<0.05), Lactate dehydrogenase (419.24±251.31 vs 257.40±177.88, P<0.05), and C-reactive protein (49.94±26.21 vs 14.58±15.25, P<0.05) signicantly improved compared with post-treatment with low-dose therapy. In addition, oxygenation index including SPO 2 (90.50±5.91 vs 97.50±1.18, P<0.05), PaO 2 (60.47±14.53 vs 99.07±34.31, P<0.05), and PaO 2 /FiO 2 (129.30±64.97 vs 340.86±146.72, P<0.05) signicant improved. Furthermore, CT showed that pulmonary lesions obviously improved in 7 patients. After systematic therapy, 4 out of 10 COVID-19 patients recovered and discharged. Conclusions: short-term moderate-dose corticosteroid COVID-19 patients who did not low-dose therapy. corticosteroid time, 160mg/d for 2-3 days, 80mg/d for 1-2 days PaO 2 2 corticosteroid


Procedures
The epidemiological, clinical, laboratory, radiographic (chest X-ray or pulmonary computed tomography, CT) and Acute Physiology Chronic Health Evaluation (APACHE ) scores were collected for all patients (Table 1). The laboratory variables included blood routine, renal and liver function, myocardial enzymes, C-reactive protein (CRP), and blood gas analysis. Pre-and post-treatment pulmonary CT were compared.

Evaluation of therapeutic effect
Indices including vital signs, laboratory markers, pulmonary CT, as well as the APACHE score were adopted to evaluate the therapeutic effect. According to the guideline from National Health Council of China, discharge and release from quarantine criteria should meet all the following requisitions: 1. afebrile for more than 3 days; 2. respiratory symptoms signi cantly relieved; 3. abnormal imaging ndings substantially improved; 4. negative COVID-19 nucleic acid test for two consecutive respiratory pathogens (sampling interval ≥1 day). 2 Statistical analysis SPSS16.0 software was adopted for statistical analysis. P <0.05 was considered statistically signi cant. Numeration data were described by number (%), and measurement data were described by mean ± standard deviation. The paired sample t test was used to evaluate the changes of clinical indexes before and after the combination of low-dose corticosteroid and immunoglobulin therapy, as well as the differences between the post-treatment with combination of moderate-dose corticosteroid and immunoglobulin and the post-treatment with low-dose therapy.

Results
A total of 10 COVID-19 patients who received a short-term moderate-dose corticosteroid plus immunoglobulin were enrolled in this study. Among them, 8 were male (80%), 2 were female (20%), with no medical staff. The age ranged from 29 to 68 year-old, with an average age of 51.60 ± 15.46 year-old.
The course of disease lasted from 2 to 30 days, with an average course of 5.40 ± 4.55 days. Clinical manifestations were diverse, and the most common symptom was fever (9 cases, 90%), followed by dry cough (6 cases, 60%). Among these 10 patients, the proportion of patients with comorbidity reached 40%. Most patients had a de nite epidemiological history, of which 4 patients (40%) exposed to Wuhan, and 6 patients (60%) exposed to Wuhan citizen. Detailed demographic and clinical characteristics of patients are shown in Table 1.
As shown in Table 2 and with pre-treatment, and the pulmonary CT showed a worsening trend, indicating that these 10 patients still suffered from continued deterioration after receiving a combination of low-dose corticosteroid and immunoglobulin. According to our experience, for patients receiving methylprednisolone 80mg/d combined with immunoglobulin 10g/d, if their condition continued to deteriorate, including a signi cant decrease in PaO 2 /FiO 2 , a obvious deterioration in pulmonary CT and / or a decrease in lymph count, a continuous high fever, the dose of methylprednisolone and immunoglobulin were increased to 160mg/d and 20g/d, respectively. It was exciting to nd that the majority of patients gradually recovered, without tracheal intubation and invasive mechanical ventilation. After short-term moderate-dose corticosteroid plus immunoglobulin treatment, all patients achieved signi cant improvement in terms of vital signs, blood work, and the APACHE scores. In detail, compared with post-treatment of low-dose corticosteroid showed signi cant improvement. In addition, the APACHE score (9.10±6.15 vs 5.50±9.01, P<0.05) was obviously reduced. Furthermore, CT showed that pulmonary lesions of obviously improved in 7 patients. These discoveries demonstrated that short-term moderate-dose corticosteroid plus immunoglobulin might effectively reverse COVID-19 patients who did not respond to low-dose therapy. For patients who received a moderate-dose corticosteroid (160mg/d), attention should be paid to reduce the dose of corticosteroid should be reduced in time, that is, methylprednisolone 160mg/d for 2-3 days, and gradually reduce to 80mg/d for 1-2 days when the PaO 2 /FiO 2 increased, followed by the maintenance dose of 40mg/d. Gradual reduction of the corticosteroid can effectively reduce the probability of secondary infection as well as to avoid disease rebound.  A typical pulmonary CT series of a patients was displayed in Figure 1. Trendgraph of important clinical variables was also shown in Figure 2. After systematic treatment, 4 out of 10 patients recovered and discharged. Only 1 death occurred in our study, and the cause of death probably was cardiac failure secondary to acute myocardial injury (Table 3).

Discussion
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 bene t 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, de ned 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 identi ed 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 in ammation 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 identi ed with no bene t 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 in ammatory 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 in ammatory response in the early stage of COVID-19 pneumonia allows low dose of corticosteroid to control the progression of in ammation effectively. Studies with low or moderate dosage therapy showed no signi cant impact in mortality rate for H7N9 cases, and low dose even bene ts 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 o cial 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 signi cantly 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 su cient to perform well in controlling in ammatory 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 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 bene ts 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 re ecting furious in ammatory 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 ndings, 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 con rmed 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 17 th to Feb 27 th , 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 in ammation 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 speci c antiviral medicines and vaccines emerge.

Declarations
Ethics approval and consent to participate This study was approved by the First Hospital of Changsha Ethics Committee. Before the survey, participants were asked to sign an informed consent to identify their willingness to take part in this study, and to ensure their rights of voluntary participation and privacy.

Consent for publication
Consent for publication was obtained.
Lei Zhang, Shu-min Xie, Jing Zhang had roles in the study design, data analysis, data interpretation, literature search, and writing of the manuscript. Zhi-Guo Zhou, Di-Xuan Jiang, Fang Zheng, Ji-Heng Liu, Chun-Lin Cai, Hui Li had roles in the clinical management, patient recruitment, data collection.

Figures
(A) Pulmonary CT image on admission; (B) Pulmonary CT images after the treatment of low-dose corticosteroid plus immunoglobulin on day 9 after onset; (C-E) Pulmonary CT images after the treatment of short-term moderate-dose corticosteroid plus immunoglobulin on day 16, 22, 30 after onset, respectively.

Figure 2
Trendgraph of important clinical variables of a COVID-19 patient respecting to the low-dose and moderate-dose corticosteroid plus immunoglobulin.