Early Tocilizumab Administration was Associated with Decreased Mortality in COVID-19 Hospitalized Patients

Early Tocilizumab Administration was Associated with Decreased Mortality in COVID-19 Hospitalized Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early Tocilizumab Administration was Associated with Decreased Mortality in COVID-19 Hospitalized Patients Shengchen DUAN, Meng ZHANG, Yan WANG, Zhechun ZENG, Huijuan ZUO, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3542200/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Coronavirus disease 2019 (COVID-19) is still prevalent at present. Tocilizumab as an effective treatment in COVID-19 is a humanized monoclonal antibody that binds to interleukin 6 (IL-6) receptor. But there is few articles that focused on the efficacious timing of tocilizumab administration. So we aimed to evaluate the efficacy of tocilizumab combined methylprednisolone in hospitalized COVID-19 patients. Methods This was a retrospective, observational cohort study. Intervention group selected patients received tocilizumab in addition to methylprednisolone treatment. Patients in the control group received standard of care treatment including methylprednisolone. The primary outcome was the patients’ clinical status, including recover rate at discharge and death rate in hospitalization. And the secondary outcome was the time from admission and methylprednisolone to tocilizumab use. Results In total, 112 patients included in this group (56 patients in the intervention group and 56 patients in the control group). The proportions of death during hospitalization was higher in the intervention group than those in the control group (p = 0.043). Both time from methylprednisolone to tocilizumab and time from admission to tocilizumab was much shorter in the recover group than that in the death group of intervention group (p = 0.004 and p = 0.008). Conclusions We found that tocilizumab was more used in COVID-19 hospitalized patients who have elevated systemic inflammation and lower Lymphocyte count. And early tocilizumab administration was associated with decreased mortality. tocilizumab Coronavirus disease 2019 interleukin-6 Figures Figure 1 1. Background Coronavirus disease 2019 (COVID-19) has been popular for 3 years since it declared a pandemic by the Word Health Organization (WHO) on March 11, 2020. The WHO reported over 770 million confirmed cases and 6.9 million deaths globally by 27 August 2023, the number of which are still on the rise. [ 1 ]Since the opening of China's COVID-19 epidemic policy on December 5, 2022, the number of confirmed COVID-19 reached a peak of 6.94 million on December 22, 2022. And it is still prevalent since then and the number of confirmed cases and deaths increases every month.[ 2 ] COVID-19 may be a seasonal disease similar to influenza that can survive for a long time in humans.[ 3 ] Therefore we still need to pay attention to this disease including its treatment. In COVID-19, acute respiratory distress syndrome (ARDS) is predominantly induced by the phenomenon of cytokine storm.[ 4 ] Hyper inflammation after viral infection could explains disease severity which begins in the second week of the disease.[ 5 ] Cytokine storm reactions are mainly related to inflammatory cytokines, especially to interleukin-6 (IL‐6), which play a major role in mediating acute lung injury leading to ARDS.[ 6 ] Tocilizumab which binds to interleukin 6 (IL-6) receptor has a role in limiting the inflammatory and immune response. The National Institutes of Health (NIH) COVID-19 treatment guidelines and the expert panels of the Infectious Disease Society of America (IDSA) have suggested that tocilizumab in addition to glucocorticoids could help improve clinical outcomes in some patients.[ 7 ][ 8 ] However, the REMAP CAP and RECOVERY data on the main basis of the above guidelines have limitations like open label design and potential bias.[ 9 ][ 10 ] On the other hand, some studies said that tocilizumab may have been underpowered to demonstrate mortality.[ 11 ][ 12 ][ 13 ] So in this study we aimed to evaluate the efficacy of tocilizumab combined methylprednisolone in hospitalized patients. In addition, there was less study focused on the efficacious timing of tocilizumab administration. Then secondly we aimed to assess the timeline for the use of tocilizumab and Methylprednisolone. 2. Methods 2.1 Study design and participants This was a retrospective, observational cohort study that took place between DEC 1, 2022 and JAN 31, 2023 in the Beijing Anzhen Hospital, Capital Medical University which is a large teaching hospital with 1600 beds. Patients were eligible for inclusion in this analysis if they were admitted to hospitalization from 1 December 2022 to 31 January 2023 for moderate to severe COVID-19 pneumonia, used methylprednisolone, and had a reverse transcriptase–polymerase chain reaction–positive SARS-CoV-2 test. Patients were excluded if they were < 18 years old, mild COVID-19 pneumonia, pregnant, died within 48 hours after hospitalization, or lung tuberculosis. This study was conducted in accordance with the Declaration of Helsinki and World Health Organization recommendations. All enrolled patients were informed and provided written consent before the study (minors were not involved). The study was approved by Anzhen Hospital of Capital Medical University ethics committee (KS2023029). 2.2 Procedures Demographics and clinical characteristics were collected on enrolment both in intervention and control group. All patients received standard of care treatment during hospitalization according to the NIH and IDSA guidelines. [ 7 ][ 8 ] Intervention group: This group selected subset of patients received tocilizumab in addition to methylprednisolone treatment who were administrated by clinical physicians. Tocilizumab was administered according Chinese guideline by the intravenous which was administered at 4–8 mg/kg bodyweight (up to a maximum of 800 mg) administered once. The second dose can be administered after 12 hours if the first dose had poor efficacy.[ 14 ] Control group: Patients in this group received standard of care treatment including methylprednisolone, and were matched one to one to intervention group patients on sex and age using the match command in Stata. 2.3 Outcome The primary outcome was the patients’ clinical status, including recover rate at discharge and death rate in hospitalization. And the secondary outcome was the time from admission and methylprednisolone to tocilizumab use. 2.4 Statistical analysis Baseline characteristics were expressed as number (proportion) or median (interquartile range) respectively and compared by χ2 test or Mann-Whitney U test where appropriate. A two-sided α less than 0.05 was considered statistically significant for all statistical tests. Statistical analyses were performed by the SPSS software, version 17.0. 3. Results 3.1 Enrollment Between DEC 1, 2022 and JAN 31, 2023, we recruited 67 COVID-19 hospitalized patients treated with tocilizumab combined methylprednisolone. After excluding 7 patients used dexamethasone, 2 patients used hydrocortisone Acetate, 2 patients died within 72 hours after hospitalization, with 56 patients included in the intervention group. After 1:1 matching based on age and gender, 56 patients treated with methylprednisolone included in the control group. (Fig. 1 ). 3.2 Primary outcomes The baseline demographic and clinical characteristics of patients are shown in Table 1 . Median length of hospital stay was significantly higher in the intervention group than in the control group (15.3 days (10.4, 23.3) vs. 12.1 days (8.1, 16.6); p = 0.008). Both the proportions of death during hospitalization and superinfection were higher in the intervention group than those in the control group (41.1%, 23/56 vs. 23.2%, 13/56; p = 0.043 and 27.3%, 15/56 vs. 5.4%, 3/56; p = 0.002). APACHE II Score and severity of illness at baseline were similar in both groups. There was no significant difference in the incidence of comorbidities between the two groups. For the laboratory test, median lymphocyte count in the intervention group was lower than that in the bacteria group (0.46×10 9 /L (0.32, 0.80) vs. 0.80×10 9 /L (0.60, 1.35); p = 0.000). Both median C-reactive protein (CRP) and IL-6 were significantly higher in the intervention group than in the control group (101.80mg/L (60.90, 154.62) vs. 66.05 mg/L (13.75, 103.20); p = 0.000 and 54.11pg/ml (18.57, 186.9) vs. 28.28pg/ml (5.29, 77.19); p = 0.020). In addition, Procalcitonin and D-Dimer showed more higher level in the intervention group than in the control group (0.31 ng/mL (0.14, 1.18) vs. 0.11ng/ml (0.07, 0.31); p = 0.000 and 903.0 ng/ml (367.0, 2199.0) vs. 461.0 ng/ml (188.0, 1167.0)). Table 1 Baseline demographic and clinical characteristics Variable Tocilizumab combined Methylprednisolone (n = 56) Methylprednisolone (n = 56) P value Age, years 73.6 ± 11.4 73.6 ± 11.4 1.000 Male(%) 42(75) 42(75) 1.000 BMI (kg/cm 2 ) 25.0(22.0, 27.0) 24.0(23.0, 26.0) 0.977 Onset of illness to admission (days) 10.0(7.0, 12.0) 9.0(6.3, 11,8) 0.218 Length of hospital stay (days) 15.3(10.4, 23.3) 12.1(8.1, 16.6) 0.008 Death during hospitalization (%) 23(41.1) 13(23.2) 0.043 APACHE II Score ≥ 15 20(35.7) 11(19.6) 0.057 < 15 36(64.3) 45(80.4) Illness Moderate 26(46.4) 34(60.7) 0.272 Severe 10(17.9) 9(16.1) Critical 20(35.7) 13(23.2) Superinfection(%) 15(27.3) 3(5.4) 0.002 Co-morbidity (%) Hypertension 10(17.9) 5(8.9) 0.165 Cardiovascular disease 7(12.5) 4(7.1) 0.341 Diabetes 8(14.3) 7(12.5) 0.781 Chronic liver disease 2(3.6) 4(7.1) 0.401 Laboratory test Oxygenation index (mmHg) 341(270, 414) 339(276, 425.5) 0.856 White blood cell count (10 9 /L) 6.90(5.00, 9.70) 7.23(5.55, 10.44) 0.481 Neutrophil count (10 9 /L) 5.91(4.02, 8.88) 5.84(3.82, 8.18) 0.758 Lymphocyte count (10 9 /L) 0.46(0.32, 0.80) 0.80(0.60, 1.35) 0.000 Haemoglobin (g/L) 119.82 ± 18.20 124.05 ± 22.60 0.599 Platelet count (G/L) 176(140.25, 229.75) 195.5(133, 280) 0.193 Creatinine (µmol/L) 82.00(61.9, 168.98) 80.25(62.88, 112.1) 0.549 Brain Natriuretic Peptide (pg/ml) 158.00(63.75, 321.75) 164.50(68.75, 394.75) 0.838 C-reactive protein(mg/L) 101.80(60.90, 154.62) 66.05(13.75, 103.20) 0.000 IL-6 (pg/ml) 54.11(18.57, 186.9) 28.28(5.29, 77.19) 0.020 Alkaline phosphatase (U/L) 82.00(65.50, 111.00) 68.5(58.75, 82.75) 0.052 Procalcitonin (ng/mL) 0.31(0.14, 1.18) 0.11(0.07, 0.31) 0.000 Lactate dehydrogenase (U/L) 320(267, 448) 320(255, 408) 0.733 Ferritin(ng/ml) 517.5(326.8, 1147) 511.0(353.3, 414.3) 0.927 D-Dimer (ng/ml) 903.0(367.0, 2199.0) 461.0(188.0, 1167.0) 0.005 Data are presented as mean ± SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables. Categorical variables were compared usingΧ 2 tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test. More patients received Albumin and γ-globulin treatment in the intervention group than those in the control group (66.1% vs. 30.4% ; p = 0.000 and 64.3% vs. 33.9% ; p = 0.001) (Table 2 ). There was no significant difference in the duration and total dose of methylprednisolone use between the two groups. Furthermore, the proportions of mechanical ventilation use was similar between two groups. Table 2 Concomitant medications and mechanical ventilation Variable Tocilizumab combined Methylprednisolone (n = 56) Methylprednisolone (n = 56) P value Concomitant medications Duration of Methylprednisolone (days) 4.0(2.5, 6.0) 4.0(2.0, 5.0) 0.333 Total dose of Methylprednisolone (mg) 160(120, 320) 160(120, 240) 0.124 Anticoagulation (%) 43(76.8) 38(67.9) 0.291 Antibiotics (%) 52(92.9) 53(94.6) 0.696 Albumin (%) 37(66.1) 17(30.4) 0.000 γ-globulin (%) 36(64.3) 19(33.9) 0.001 Baricitinib (%) 5(8.9) 3(5.4) 0.463 Mechanical ventilation NIPPV or HFNC (%) 32(57.1) 25(44.6) 0.298 IMV (%) 14(25.0) 10(17.9) 0.357 NIPPV, noninvasive positive pressure ventilation; HFNC, High flow nasal cannula; IMV, Invasive mechanical ventilation Data are presented as mean ± SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables. Categorical variables were compared usingΧ 2 tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test. 3.3 Secondary outcomes We compared the baseline demographic and clinical characteristics of outcome in the intervention group(Table 3 ). The proportions of critical illness patients was lower in the recover group (3.0% vs. 82.6%; p = 0.000). There was no significant difference in the other baseline demographic. Both white blood cell count and neutrophil count were significantly lower in the recover group than in the death group (5.52×109/L vs. 9.18×109/L; p = 0.000 and 4.88×109/L vs. 8.15 ×109/L; p = 0.001). Table 3 Baseline demographic and clinical characteristics with intervention group Variable Tocilizumab combined Methylprednisolone (n = 56) P value Recover (n = 33) Death (n = 23) Age, years 70.91 ± 11.0 77.39 ± 11.1 0.749 Male(%) 23(69.7) 19(82.6) 0.272 BMI (kg/cm 2 ) 24.78 ± 4.0 23.76 ± 3.7 0.906 Onset of illness to admission (days) 10.0(7.0, 12.0) 10.0(7.0, 14.0) 0.756 Length of hospital stay (days) 15.15(9.84, 23.9) 15.5(10.89, 21.76) 0.696 Illness Moderate + Severe 32(97.0) 4(17.4) 0.000 Critical 1(3.0) 19(82.6) Superinfection(%) 7(21.9) 8(34.8) 0.289 Cardiovascular disease 7(21.2) 3(13.0) 0.432 Diabetes 5(15.2) 2(8.7) 0.472 Chronic liver disease 8(24.2) 2(8.7) 0.135 Laboratory test Oxygenation index (mmHg) 365.18 ± 109.56 334.13 ± 120.16 0.325 White blood cell count (10 9 /L) 5.52(4.36, 8.37) 9.18(6.84, 10.65) 0.002 Neutrophil count (10 9 /L) 4.88(3.53, 7.02) 8.15(6.02, 9.58) 0.001 Lymphocyte count (10 9 /L) 0.55(0.38, 0.85) 0.40(0.26, 0.60) 0.154 Creatinine (µmol/L) 91.5(58.45, 531.2) 75.40(65.10, 123.30) 0.306 Brain Natriuretic Peptide (pg/ml) 163.5(83.25, 384.5) 155.50(52.75, 267.00) 0.507 C-reactive protein(mg/L) 94.01(59.43, 152.04) 111.64(69.05, 186.47) 0.611 IL-6 (pg/ml) PCT 54.11(21.09, 121.69) 57.19(16.95, 261.86) 0.668 Data are presented as mean ± SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables. Categorical variables were compared usingΧ 2 tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test. For the concomitant medications of intervention group, total dose of methylprednisolone was much lower in the recover group than in the death group (160.0mg (80.0, 320.0) vs. 280.0mg (160.0, 320.0); p = 0.009)(Table 4 ). Both time from methylprednisolone to tocilizumab and time from admission to tocilizumab was much shorter in the recover group than that in the death group(1.0 day (0, 3.5) vs. 5.0 days(1.0, 7.0); p = 0.004 and 3.0(1.0, 6.0) vs. 6.0(4.0, 10.0); p = 0.008). In addition, less patients received albumin and γ-globulin treatment in the recover group than those in the death group (48.5% vs. 91.3% ; p = 0.001 and 51.5% vs. 82.6% ; p = 0.017). Table 4 Concomitant medications with intervention group Variable Tocilizumab combined Methylprednisolone (n = 56) P value Recover (n = 33) Death (n = 23) Concomitant medications Duration of Methylprednisolone (days) 4.0(3.0, 6.0) 4.0(2.0, 7.5) 0.287 Total dose of Methylprednisolone (mg) 160.0(80.0, 320.0) 280.0(160.0, 320.0) 0.009 Time from methylprednisolone to tocilizumab (days) 1.0(0, 3.5) 5.0(1.0, 7.0) 0.004 Time from admission to tocilizumab (days) 3.0(1.0, 6.0) 6.0(4.0, 10.0) 0.008 Anticoagulation (%) 23(69.7) 20(87.0) 0.132 Antibiotics (%) 33(100) 23(100) - Albumin (%) 16(48.5) 21(91.3) 0.001 γ-globulin (%) 17(51.5) 19(82.6) 0.017 Baricitinib (%) 1(3.0) 4(17.4) 0.064 Data are presented as mean ± SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables. Categorical variables were compared usingΧ 2 tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test. 4. Discussion In this retrospective, observational study, receipt of tocilizumab seems to be unrelated with improved survival.Tocilizumab was also associated with increased incidence of secondary bacterial pneumonia, but it did not increase mortality. Tocilizumab was more likely used in COVID-19 hospitalized patients who have elevated systemic inflammation (CRP and IL-6) and lower Lymphocyte count. Higher doses of methylprednisolone do not seem to be helpful for outcome. We highlight that tocilizumab should be used as soon as possible after hospitalization admission and after methylprednisolone use if it is administrated. Our study did not find any advantages of tocilizumab over the conventional treatment (methylprednisolone use) in terms of mortality or length of hospital stay. In fact, some previous important randomized clinical trials (RCT) showed controversial outcomes and had their limitations respectly.[ 9 ][ 10 ][ 12 ][ 13 ] Stone et al.[ 12 ] and Salvarini et al. [ 13 ]had a low mortality rate in their population and any conclusions should be taken with caution and must not be generalised to the overall COVID-19 population, which believes that tocilizumab is not associated with reducing mortality.[ 6 ] Meanwhile, both REMAP-CAP and RECOVERY which had positive results were open label design, and clinical severity classification heterogeneity also existed. But more opinions thought a possible association betwereen tocilizumab and lower mortality.[ 15 ][ 8 ][ 7 ] Some reasons can be explained in our study. Fistly, this is a retrospective observational study. Secondly, our study showed higher inflammatory storms in the tocilizumab group in which CRP and IL-6 were more higher and Lymphocyte count was much lower. And the high level of inflammatory storm may be related to the worse prognosis of patients and this may induce results of heterogeneity in the two groups .[ 11 ] Therefore, better RCT need to be designed to confirm this point. To our knowledge, this is the first study focused on the efficacious timing of tocilizumab administration including Critical and non critical COVID-19 patients. We found tocilizumab should be used as soon as possible after hospitalization admission and after methylprednisolone administration if it was administrated. Petrak et al. supported a clinical benefit of early tocilizumab treatment, within the first day of intubation, and a possible detriment to later administration[ 16 ]. However, this study only focused on patients with critical illness COVID-19 who were intubated. Early and late tocilizumab dosing was defined as a 1 day of intubation which would omit some information and induced bias. A review thought the benefit of tocilizumab treatment in REMAP-CAP trial and RECOVERY trials was associated with early administration in the clinical course of illness: 2 days of hospitalization in RECOVERY and < 24 h in the ICU for REMAP-CAP.[ 15 ][ 9 ][ 10 ] However, the above data is only reflected in the results, and neither above studies were not any efficacious timing of tocilizumab administration designs, which seems to be a less rigorous conclusion. As a result, our results were more trustworthy. We acknowledged that our research had some limitations. Firstly, the retrospective and single-center study design may have introduced patient selection bias and affected the study results, the results of which need to be verified by future RCT multicentre studies. Secondly, We did not conduct subgroup analysis after illness stratification. Furthermore, this study was conducted at the time of the outbreak of COVID-19 in China, when medical resources were relatively scarce, and there were also patients with critical illness or intubation in ordinary wards. Therefore, the transfer rate of intensive care unit (ICU) was not analyzed. 5. Conclusion In conclusion, we found that tocilizumab was more used in COVID-19 hospitalized patients who have elevated systemic inflammation (CRP and IL-6) and lower Lymphocyte count. And early tocilizumab administration was associated with decreased mortality. Abbreviations COVID-19: Coronavirus disease 2019; IL-6: interleukin 6; WHO: Word Health Organization; ARDS: acute respiratory distress syndrome; NIH: National Institutes of Health; IDSA: Infectious Disease Society of America; CRP: C-reactive protein; RCT: randomized clinical trial; ICU: intensive care unit Declarations Acknowledgments We thank all the COVID-19 patients and clinical staff in the general wards and ICUs of Anzhen Hospital for receiving COVID-19 patients and laboratory of Clinical Microbiology and Infectious Diseases in Anzhen Hospital, including clinicians, nurses and laboratory technicians. Funding This work was supported by the Key Program of Beijing Natural Science Foundation of China (NO. Z220019) and CAMS Innovation Fund for Medical Sciences (CIFMS) (NO. 2021‐I2M‐1‐049) Availability of data and materials As other investigations involving this data are in progress, the data will not be available to others at present. When all investigations are finished, the data will be made available on reasonable request by contacting corresponding author. Authors` contributors Shengchen DUAN designed the trial, reviewed the medical literature, participated in the data analysis and interpretation, and drafted and wrote the manuscript. Meng ZHANG participated in the data analysis. Yan WANG participated in the data analysis. Zhechun ZENG carried out statistical analysis of the data. Huijuan ZUO carried out statistical analysis of the data. Jun WAN conceived, designed, supervised and allocated staff to the trial, and participated in data analysis and interpretation. All authors reviewed and contributed to the manuscript during its development. Ethics approval and consent to participate All enrolled patients were informed and provided written consent before the study (minors were not involved). The study was approved by Anzhen Hospital of Capital Medical University ethics committee (KS2023029). Consent for publication Not applicable. Competing interests The authors of the manuscript declare no conflicts of interest and take sole responsibility for the writing and content of the manuscript. None of the authors have been involved in legal or regulatory matters related to the contents of this paper. References WHO. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-september-2023. https://www.chinacdc.cn/jkzt/crb/zl/szkb_11803/jszl_13141/202309/t20230906_269361.html. Tomaszewski T, Ali MA, Caetano-Anollés K, Caetano-Anollés G. Seasonal effects decouple SARS-CoV-2 haplotypes worldwide. F1000Research. 2023;12:1–32. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’’ in COVID-19.’ J Infect. 2020;80:607–13. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J Hear Lung Transplant. 2020;39:405–7. 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Expert Rev Clin Pharmacol. 2021;14:1279–87. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020;383:2333–44. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized with COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181:24–31. https://www.gov.cn/zhengce/zhengceku/2023-01/06/content_5735343.htm. Yu SY, Koh DH, Choi M, Ryoo S, Huh K, Yeom JS, et al. Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis. Emerg Microbes Infect. 2022;11:1154–65. Petrak RM, Van Hise NW, Skorodin NC, Fliegelman RM, Chundi V, Didwania V, et al. Early Tocilizumab Dosing Is Associated With Improved Survival in Critically Ill Patients Infected With Severe Acute Respiratory Syndrome Coronavirus-2. Crit Care Explor. 2021;3:e0395. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3542200","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":246709443,"identity":"36c8ffa9-586e-48fd-8710-18783b6d0f0e","order_by":0,"name":"Shengchen DUAN","email":"","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shengchen","middleName":"","lastName":"DUAN","suffix":""},{"id":246709444,"identity":"ca7f72ea-a4b2-4dff-b612-31143b5fc149","order_by":1,"name":"Meng ZHANG","email":"","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"ZHANG","suffix":""},{"id":246709445,"identity":"467b64b9-4e29-421c-8c73-e34a988f6fa4","order_by":2,"name":"Yan WANG","email":"","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"WANG","suffix":""},{"id":246709447,"identity":"6b95ac50-09da-401a-9660-91517a6149a6","order_by":3,"name":"Zhechun ZENG","email":"","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhechun","middleName":"","lastName":"ZENG","suffix":""},{"id":246709449,"identity":"4eadca95-6204-43df-9d8a-1a4186103825","order_by":4,"name":"Huijuan ZUO","email":"","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Huijuan","middleName":"","lastName":"ZUO","suffix":""},{"id":246709451,"identity":"353ac58e-fca5-4d0c-8ebf-22a7fa5f465d","order_by":5,"name":"Jun WAN","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYBACxgYwZcPDz8x8gCQtaXKS7WwJJFl22NjgPI8BcWqZZ+Qek/i5gzmx4TDPxxtvGOzkdBsIOWxGXppk7xm2xMZm3s2WcxiSjc0OENSSY3aDt40nsZmZd5s0D8OBxG3EaLn5t00isY2Z5xnxWm7zthkY8zDzsBGppeeN+W/ZtgQ5CWY2Y8s5BkT4xbA9x9jwbdt/Hvvzhx/eeFNhJ0dYSwMSR4KoqJFH5kjwEKFjFIyCUTAKRh4AAMPOPduqGSo9AAAAAElFTkSuQmCC","orcid":"","institution":"Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"WAN","suffix":""}],"badges":[],"createdAt":"2023-11-02 08:44:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3542200/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3542200/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":46116937,"identity":"c6549ea4-fd23-40df-8574-de221c8c07a0","added_by":"auto","created_at":"2023-11-08 21:39:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":177395,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial profile\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3542200/v1/ee1b65f0aa94fffac4b92290.png"},{"id":48841074,"identity":"dc95e129-1f7a-4a65-8e42-3baf6e7cef3f","added_by":"auto","created_at":"2023-12-27 07:07:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":518542,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3542200/v1/4c002f47-d3f7-49c3-a296-2728b47eac95.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early Tocilizumab Administration was Associated with Decreased Mortality in COVID-19 Hospitalized Patients","fulltext":[{"header":"1. Background","content":"\u003cp\u003eCoronavirus disease 2019 (COVID-19) has been popular for 3 years since it declared a pandemic by the Word Health Organization (WHO) on March 11, 2020. The WHO reported over 770\u0026nbsp;million confirmed cases and 6.9\u0026nbsp;million deaths globally by 27 August 2023, the number of which are still on the rise. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]Since the opening of China's COVID-19 epidemic policy on December 5, 2022, the number of confirmed COVID-19 reached a peak of 6.94\u0026nbsp;million on December 22, 2022. And it is still prevalent since then and the number of confirmed cases and deaths increases every month.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] COVID-19 may be a seasonal disease similar to influenza that can survive for a long time in humans.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Therefore we still need to pay attention to this disease including its treatment.\u003c/p\u003e \u003cp\u003eIn COVID-19, acute respiratory distress syndrome (ARDS) is predominantly induced by the phenomenon of cytokine storm.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Hyper inflammation after viral infection could explains disease severity which begins in the second week of the disease.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Cytokine storm reactions are mainly related to inflammatory cytokines, especially to interleukin-6 (IL‐6), which play a major role in mediating acute lung injury leading to ARDS.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Tocilizumab which binds to interleukin 6 (IL-6) receptor has a role in limiting the inflammatory and immune response.\u003c/p\u003e \u003cp\u003e The National Institutes of Health (NIH) COVID-19 treatment guidelines and the expert panels of the Infectious Disease Society of America (IDSA) have suggested that tocilizumab in addition to glucocorticoids could help improve clinical outcomes in some patients.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] However, the REMAP CAP and RECOVERY data on the main basis of the above guidelines have limitations like open label design and potential bias.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] On the other hand, some studies said that tocilizumab may have been underpowered to demonstrate mortality.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] So in this study we aimed to evaluate the efficacy of tocilizumab combined methylprednisolone in hospitalized patients. In addition, there was less study focused on the efficacious timing of tocilizumab administration. Then secondly we aimed to assess the timeline for the use of tocilizumab and Methylprednisolone.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and participants\u003c/h2\u003e \u003cp\u003eThis was a retrospective, observational cohort study that took place between DEC 1, 2022 and JAN 31, 2023 in the Beijing Anzhen Hospital, Capital Medical University which is a large teaching hospital with 1600 beds. Patients were eligible for inclusion in this analysis if they were admitted to hospitalization from 1 December 2022 to 31 January 2023 for moderate to severe COVID-19 pneumonia, used methylprednisolone, and had a reverse transcriptase\u0026ndash;polymerase chain reaction\u0026ndash;positive SARS-CoV-2 test. Patients were excluded if they were \u0026lt;\u0026thinsp;18 years old, mild COVID-19 pneumonia, pregnant, died within 48 hours after hospitalization, or lung tuberculosis.\u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and World Health Organization recommendations. All enrolled patients were informed and provided written consent before the study (minors were not involved). The study was approved by Anzhen Hospital of Capital Medical University ethics committee (KS2023029).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Procedures\u003c/h2\u003e \u003cp\u003eDemographics and clinical characteristics were collected on enrolment both in intervention and control group. All patients received standard of care treatment during hospitalization according to the NIH and IDSA guidelines. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIntervention group: This group selected subset of patients received tocilizumab in addition to methylprednisolone treatment who were administrated by clinical physicians. Tocilizumab was administered according Chinese guideline by the intravenous which was administered at 4\u0026ndash;8 mg/kg bodyweight (up to a maximum of 800 mg) administered once. The second dose can be administered after 12 hours if the first dose had poor efficacy.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e Control group: Patients in this group received standard of care treatment including methylprednisolone, and were matched one to one to intervention group patients on sex and age using the match command in Stata.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome was the patients\u0026rsquo; clinical status, including recover rate at discharge and death rate in hospitalization. And the secondary outcome was the time from admission and methylprednisolone to tocilizumab use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eBaseline characteristics were expressed as number (proportion) or median (interquartile range) respectively and compared by χ2 test or Mann-Whitney U test where appropriate. A two-sided α less than 0.05 was considered statistically significant for all statistical tests. Statistical analyses were performed by the SPSS software, version 17.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Enrollment\u003c/h2\u003e \u003cp\u003eBetween DEC 1, 2022 and JAN 31, 2023, we recruited 67 COVID-19 hospitalized patients treated with tocilizumab combined methylprednisolone. After excluding 7 patients used dexamethasone, 2 patients used hydrocortisone Acetate, 2 patients died within 72 hours after hospitalization, with 56 patients included in the intervention group. After 1:1 matching based on age and gender, 56 patients treated with methylprednisolone included in the control group. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Primary outcomes\u003c/h2\u003e \u003cp\u003eThe baseline demographic and clinical characteristics of patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Median length of hospital stay was significantly higher in the intervention group than in the control group (15.3 days (10.4, 23.3) vs. 12.1 days (8.1, 16.6); p\u0026thinsp;=\u0026thinsp;0.008). Both the proportions of death during hospitalization and superinfection were higher in the intervention group than those in the control group (41.1%, 23/56 vs. 23.2%, 13/56; p\u0026thinsp;=\u0026thinsp;0.043 and 27.3%, 15/56 vs. 5.4%, 3/56; p\u0026thinsp;=\u0026thinsp;0.002). APACHE II Score and severity of illness at baseline were similar in both groups. There was no significant difference in the incidence of comorbidities between the two groups. For the laboratory test, median lymphocyte count in the intervention group was lower than that in the bacteria group (0.46\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L (0.32, 0.80) vs. 0.80\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L (0.60, 1.35); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000). Both median C-reactive protein (CRP) and IL-6 were significantly higher in the intervention group than in the control group (101.80mg/L (60.90, 154.62) vs. 66.05 mg/L (13.75, 103.20); p\u0026thinsp;=\u0026thinsp;0.000 and 54.11pg/ml (18.57, 186.9) vs. 28.28pg/ml (5.29, 77.19); p\u0026thinsp;=\u0026thinsp;0.020). In addition, Procalcitonin and D-Dimer showed more higher level in the intervention group than in the control group (0.31 ng/mL (0.14, 1.18) vs. 0.11ng/ml (0.07, 0.31); p\u0026thinsp;=\u0026thinsp;0.000 and 903.0 ng/ml (367.0, 2199.0) vs. 461.0 ng/ml (188.0, 1167.0)).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTocilizumab combined Methylprednisolone \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMethylprednisolone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42(75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42(75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.0(22.0, 27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0(23.0, 26.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.977\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset of illness to admission (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0(7.0, 12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0(6.3, 11,8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.218\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.3(10.4, 23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.1(8.1, 16.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath during hospitalization (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.043\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE\u0026nbsp;II\u0026nbsp;Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36(64.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45(80.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIllness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(46.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34(60.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(16.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCritical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(23.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuperinfection(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo-morbidity (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic liver disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygenation index (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e341(270, 414)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e339(276, 425.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.856\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood cell count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.90(5.00, 9.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.23(5.55, 10.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.481\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.91(4.02, 8.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.84(3.82, 8.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.46(0.32, 0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.80(0.60, 1.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemoglobin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119.82\u0026thinsp;\u0026plusmn;\u0026thinsp;18.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.05\u0026thinsp;\u0026plusmn;\u0026thinsp;22.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.599\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count (G/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176(140.25, 229.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e195.5(133, 280)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82.00(61.9, 168.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.25(62.88, 112.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.549\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain Natriuretic Peptide (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158.00(63.75, 321.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e164.50(68.75, 394.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.838\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein(mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101.80(60.90, 154.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.05(13.75, 103.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.11(18.57, 186.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.28(5.29, 77.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline phosphatase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82.00(65.50, 111.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.5(58.75, 82.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcalcitonin (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31(0.14, 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11(0.07, 0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate dehydrogenase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e320(267, 448)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e320(255, 408)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.733\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e517.5(326.8, 1147)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e511.0(353.3, 414.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.927\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-Dimer (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e903.0(367.0, 2199.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e461.0(188.0, 1167.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCategorical variables were compared usingΧ\u003csup\u003e2\u003c/sup\u003e tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMore patients received Albumin and γ-globulin treatment in the intervention group than those in the control group (66.1% vs. 30.4% ; p\u0026thinsp;=\u0026thinsp;0.000 and 64.3% vs. 33.9% ; p\u0026thinsp;=\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no significant difference in the duration and total dose of methylprednisolone use between the two groups. Furthermore, the proportions of mechanical ventilation use was similar between two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eConcomitant medications and mechanical ventilation\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTocilizumab combined Methylprednisolone \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMethylprednisolone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of Methylprednisolone (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0(2.5, 6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0(2.0, 5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal dose of Methylprednisolone (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160(120, 320)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160(120, 240)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43(76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(67.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.291\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52(92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53(94.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.696\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37(66.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17(30.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-globulin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36(64.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaricitinib (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.463\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIPPV or HFNC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25(44.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.298\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMV (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNIPPV, noninvasive positive pressure ventilation; HFNC, High flow nasal cannula; IMV, Invasive mechanical ventilation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCategorical variables were compared usingΧ\u003csup\u003e2\u003c/sup\u003e tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Secondary outcomes\u003c/h2\u003e \u003cp\u003eWe compared the baseline demographic and clinical characteristics of outcome in the intervention group(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The proportions of critical illness patients was lower in the recover group (3.0% vs. 82.6%; p\u0026thinsp;=\u0026thinsp;0.000). There was no significant difference in the other baseline demographic. Both white blood cell count and neutrophil count were significantly lower in the recover group than in the death group (5.52\u0026times;109/L vs. 9.18\u0026times;109/L; p\u0026thinsp;=\u0026thinsp;0.000 and 4.88\u0026times;109/L vs. 8.15 \u0026times;109/L; p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic and clinical characteristics with intervention group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTocilizumab combined Methylprednisolone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecover\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.91\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.39\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(69.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.78\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.76\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.906\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset of illness to admission (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0(7.0, 12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.0(7.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.756\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.15(9.84, 23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.5(10.89, 21.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.696\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIllness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u0026thinsp;+\u0026thinsp;Severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(97.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCritical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(82.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuperinfection(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(21.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.472\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic liver disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygenation index (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e365.18\u0026thinsp;\u0026plusmn;\u0026thinsp;109.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e334.13\u0026thinsp;\u0026plusmn;\u0026thinsp;120.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.325\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood cell count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.52(4.36, 8.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.18(6.84, 10.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.88(3.53, 7.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.15(6.02, 9.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.55(0.38, 0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40(0.26, 0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.154\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91.5(58.45, 531.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.40(65.10, 123.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.306\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain Natriuretic Peptide (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e163.5(83.25, 384.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e155.50(52.75, 267.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.507\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein(mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94.01(59.43, 152.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111.64(69.05, 186.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e \u003cp\u003ePCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.11(21.09, 121.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.19(16.95, 261.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.668\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCategorical variables were compared usingΧ\u003csup\u003e2\u003c/sup\u003e tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor the concomitant medications of intervention group, total dose of methylprednisolone was much lower in the recover group than in the death group (160.0mg (80.0, 320.0) vs. 280.0mg (160.0, 320.0); p\u0026thinsp;=\u0026thinsp;0.009)(Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Both time from methylprednisolone to tocilizumab and time from admission to tocilizumab was much shorter in the recover group than that in the death group(1.0 day (0, 3.5) vs. 5.0 days(1.0, 7.0); p\u0026thinsp;=\u0026thinsp;0.004 and 3.0(1.0, 6.0) vs. 6.0(4.0, 10.0); p\u0026thinsp;=\u0026thinsp;0.008). In addition, less patients received albumin and γ-globulin treatment in the recover group than those in the death group (48.5% vs. 91.3% ; p\u0026thinsp;=\u0026thinsp;0.001 and 51.5% vs. 82.6% ; p\u0026thinsp;=\u0026thinsp;0.017).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eConcomitant medications with intervention group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTocilizumab combined Methylprednisolone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecover\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of Methylprednisolone (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0(3.0, 6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0(2.0, 7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal dose of Methylprednisolone (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160.0(80.0, 320.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e280.0(160.0, 320.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from methylprednisolone to tocilizumab (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0(0, 3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0(1.0, 7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from admission to tocilizumab (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0(1.0, 6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0(4.0, 10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(69.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20(87.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(48.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21(91.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-globulin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaricitinib (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (standard deviation) or as median (interquartile range) for continuous variables and as percent for categorical variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCategorical variables were compared usingΧ\u003csup\u003e2\u003c/sup\u003e tests, and continuous variables were compared using Wilcoxon rank-sum test or Student's t-test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this retrospective, observational study, receipt of tocilizumab seems to be unrelated with improved survival.Tocilizumab was also associated with increased incidence of secondary bacterial pneumonia, but it did not increase mortality. Tocilizumab was more likely used in COVID-19 hospitalized patients who have elevated systemic inflammation (CRP and IL-6) and lower Lymphocyte count. Higher doses of methylprednisolone do not seem to be helpful for outcome. We highlight that tocilizumab should be used as soon as possible after hospitalization admission and after methylprednisolone use if it is administrated.\u003c/p\u003e \u003cp\u003eOur study did not find any advantages of tocilizumab over the conventional treatment (methylprednisolone use) in terms of mortality or length of hospital stay. In fact, some previous important randomized clinical trials (RCT) showed controversial outcomes and had their limitations respectly.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Stone et al.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and Salvarini et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]had a low mortality rate in their population and any conclusions should be taken with caution and must not be generalised to the overall COVID-19 population, which believes that tocilizumab is not associated with reducing mortality.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Meanwhile, both REMAP-CAP and RECOVERY which had positive results were open label design, and clinical severity classification heterogeneity also existed. But more opinions thought a possible association betwereen tocilizumab and lower mortality.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Some reasons can be explained in our study. Fistly, this is a retrospective observational study. Secondly, our study showed higher inflammatory storms in the tocilizumab group in which CRP and IL-6 were more higher and Lymphocyte count was much lower. And the high level of inflammatory storm may be related to the worse prognosis of patients and this may induce results of heterogeneity in the two groups .[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Therefore, better RCT need to be designed to confirm this point.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study focused on the efficacious timing of tocilizumab administration including Critical and non critical COVID-19 patients. We found tocilizumab should be used as soon as possible after hospitalization admission and after methylprednisolone administration if it was administrated. Petrak et al. supported a clinical benefit of early tocilizumab treatment, within the first day of intubation, and a possible detriment to later administration[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, this study only focused on patients with critical illness COVID-19 who were intubated. Early and late tocilizumab dosing was defined as a 1 day of intubation which would omit some information and induced bias. A review thought the benefit of tocilizumab treatment in REMAP-CAP trial and RECOVERY trials was associated with early administration in the clinical course of illness: 2 days of hospitalization in RECOVERY and \u0026lt;\u0026thinsp;24 h in the ICU for REMAP-CAP.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] However, the above data is only reflected in the results, and neither above studies were not any efficacious timing of tocilizumab administration designs, which seems to be a less rigorous conclusion. As a result, our results were more trustworthy.\u003c/p\u003e \u003cp\u003eWe acknowledged that our research had some limitations. Firstly, the retrospective and single-center study design may have introduced patient selection bias and affected the study results, the results of which need to be verified by future RCT multicentre studies. Secondly, We did not conduct subgroup analysis after illness stratification. Furthermore, this study was conducted at the time of the outbreak of COVID-19 in China, when medical resources were relatively scarce, and there were also patients with critical illness or intubation in ordinary wards. Therefore, the transfer rate of intensive care unit (ICU) was not analyzed.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn conclusion, we found that tocilizumab was more used in COVID-19 hospitalized patients who have elevated systemic inflammation (CRP and IL-6) and lower Lymphocyte count. And early tocilizumab administration was associated with decreased mortality.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOVID-19: Coronavirus disease 2019; IL-6: interleukin 6; WHO: Word Health Organization; ARDS: acute respiratory distress syndrome; NIH: National Institutes of Health; IDSA: Infectious Disease Society of America; CRP: C-reactive protein; RCT: randomized clinical trial; ICU: intensive care unit\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the COVID-19 patients and clinical staff in the\u0026nbsp;general wards and ICUs of\u0026nbsp;Anzhen Hospital for receiving COVID-19 patients and\u0026nbsp;laboratory of Clinical Microbiology and Infectious Diseases\u0026nbsp;in\u0026nbsp;Anzhen Hospital, including clinicians, nurses and laboratory technicians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Key Program of Beijing Natural Science Foundation of China (NO. Z220019) and CAMS Innovation Fund for Medical Sciences (CIFMS) (NO. 2021‐I2M‐1‐049)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs other investigations involving this data are in progress, the data will not be available to others at present. When all investigations are finished, the data will be made available on reasonable request by contacting corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors` contributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShengchen DUAN\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003edesigned the trial, reviewed the medical literature, participated in the data analysis and interpretation, and drafted and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeng ZHANG\u003c/strong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eparticipated in the data analysis.\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYan WANG\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eparticipated in the data analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eZhechun ZENG\u003c/strong\u003e carried out statistical analysis of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuijuan ZUO\u003c/strong\u003e carried out statistical analysis of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJun WAN\u003c/strong\u003e conceived, designed, supervised and allocated staff to the trial, and participated in data analysis and interpretation.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and contributed to the manuscript during its development.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll enrolled patients were informed and provided written consent before the study (minors were not involved).\u0026nbsp;The study was approved by Anzhen Hospital of Capital Medical University ethics committee (KS2023029).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors of the manuscript declare no conflicts of interest and take sole responsibility for the writing and content of the manuscript. None of the authors have been involved in legal or regulatory matters related to the contents of this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-september-2023.\u003c/li\u003e\n\u003cli\u003ehttps://www.chinacdc.cn/jkzt/crb/zl/szkb_11803/jszl_13141/202309/t20230906_269361.html.\u003c/li\u003e\n\u003cli\u003eTomaszewski T, Ali MA, Caetano-Anoll\u0026eacute;s K, Caetano-Anoll\u0026eacute;s G. Seasonal effects decouple SARS-CoV-2 haplotypes worldwide. F1000Research. 2023;12:1\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eYe Q, Wang B, Mao J. The pathogenesis and treatment of the \u0026lsquo;Cytokine Storm\u0026rsquo;\u0026rsquo; in COVID-19.\u0026rsquo; J Infect. 2020;80:607\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eSiddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical\u0026ndash;therapeutic staging proposal. J Hear Lung Transplant. 2020;39:405\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eKlopfenstein T, Gendrin V, Kadiane-Oussou NJ, Conrozier T, Zayet S. Tocilizumab in COVID-19 pneumonia: Practical proposals based on a narrative review of randomised trials. Rev Med Virol. 2022;32:1\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBhimraj A, Morgan RL, Shumaker AH, Baden LR, Cheng VC, Edwards KM, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With Coronavirus Disease 2019 ( COVID-19 ). 2019;2019:1\u0026ndash;100.\u003c/li\u003e\n\u003cli\u003eGuidelines T. Coronavirus Disease 2019 ( COVID-19 ) Treatment Guidelines. 2019;2019.\u003c/li\u003e\n\u003cli\u003eAbani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397:1637\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eInterleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384:1491\u0026ndash;502.\u003c/li\u003e\n\u003cli\u003eKenny G, Mallon PWG. Tocilizumab for the treatment of non‐critical COVID‐19 pneumonia: an overview of the rationale and clinical evidence to date. Expert Rev Clin Pharmacol. 2021;14:1279\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eStone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020;383:2333\u0026ndash;44.\u003c/li\u003e\n\u003cli\u003eSalvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized with COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181:24\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003ehttps://www.gov.cn/zhengce/zhengceku/2023-01/06/content_5735343.htm.\u003c/li\u003e\n\u003cli\u003eYu SY, Koh DH, Choi M, Ryoo S, Huh K, Yeom JS, et al. Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis. Emerg Microbes Infect. 2022;11:1154\u0026ndash;65.\u003c/li\u003e\n\u003cli\u003ePetrak RM, Van Hise NW, Skorodin NC, Fliegelman RM, Chundi V, Didwania V, et al. Early Tocilizumab Dosing Is Associated With Improved Survival in Critically Ill Patients Infected With Severe Acute Respiratory Syndrome Coronavirus-2. Crit Care Explor. 2021;3:e0395.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"tocilizumab, Coronavirus disease 2019, interleukin-6","lastPublishedDoi":"10.21203/rs.3.rs-3542200/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3542200/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCoronavirus disease 2019 (COVID-19) is still prevalent at present. Tocilizumab as an effective treatment in COVID-19 is a humanized monoclonal antibody that binds to interleukin 6 (IL-6) receptor. But there is few articles that focused on the efficacious timing of tocilizumab administration. So we aimed to evaluate the efficacy of tocilizumab combined methylprednisolone in hospitalized COVID-19 patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a retrospective, observational cohort study. Intervention group selected patients received tocilizumab in addition to methylprednisolone treatment. Patients in the control group received standard of care treatment including methylprednisolone. The primary outcome was the patients\u0026rsquo; clinical status, including recover rate at discharge and death rate in hospitalization. And the secondary outcome was the time from admission and methylprednisolone to tocilizumab use.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 112 patients included in this group (56 patients in the intervention group and 56 patients in the control group). The proportions of death during hospitalization was higher in the intervention group than those in the control group (p\u0026thinsp;=\u0026thinsp;0.043). Both time from methylprednisolone to tocilizumab and time from admission to tocilizumab was much shorter in the recover group than that in the death group of intervention group (p\u0026thinsp;=\u0026thinsp;0.004 and p\u0026thinsp;=\u0026thinsp;0.008).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe found that tocilizumab was more used in COVID-19 hospitalized patients who have elevated systemic inflammation and lower Lymphocyte count. And early tocilizumab administration was associated with decreased mortality.\u003c/p\u003e","manuscriptTitle":"Early Tocilizumab Administration was Associated with Decreased Mortality in COVID-19 Hospitalized Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-08 21:39:15","doi":"10.21203/rs.3.rs-3542200/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89730c2e-fec4-4c55-bde9-921d73f6ef97","owner":[],"postedDate":"November 8th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-07T13:15:28+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-08 21:39:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3542200","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3542200","identity":"rs-3542200","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}