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Tocilizumab Treatment Reduces Mortality in Hospitalized Patients With COVID-19: A Retrospective Cohort Study at a New York City Hospital

Aims This study aimed to investigate the potential of tocilizumab therapy in minimizing mortality and mechanical ventilation (MV) requirements among hospitalized COVID-19 patients. Methods A single-center, retrospective, observational cohort study of 375 patients with severe COVID-19 (from March 1 to April 22, 2020) included 150 patients treated with tocilizumab and 225 consecutive control patients adjusted for age and sex. Both groups received concomitant standard of care treatments in addition to tocilizumab. The statistical methods relied on survival analyses, conditional logistic regression models, and contingency analyses. The outcomes included in-hospital mortality and the MV requirement. Results Tocilizumab associated with improved in-hospital mortality (34.7% vs 46.7%, P = 0.0136) and lower requirement for MV on days 1, 3, and 5 after treatment (P = 0.005, P < 0.0001, and P = 0.0021, respectively). Lower mortality was observed if tocilizumab was administered within 48 hours after admission (P = 0.0226). Older age and low blood oxygen saturation on admission decreased the odds of survival (P < 0.005). Conclusions Our study demonstrates a significant reduction in mortality and decreased requirement of MV with tocilizumab treatment in addition to the standard of care. Early administration of tocilizumab within 48 hours reduces the risk of mortality.

case identified in the United States in January 2020. The steadfast global expansion of the COVID-19 pandemic has created an urgent need for effective evidence-based therapies. 1,2 A mounting body of evidence suggests that a subgroup of patients with SARS-CoV-2 may deteriorate clinically because of a proinflammatory cytokine storm syndrome. 3,4 An overwhelming release of cytokines such as interleukin 6 (IL-6), tumor necrosis factor α, IL-12, and IL-1 5 leads to an increase in alveolar exudate, acute respiratory distress syndrome, and multiorgan dysfunction. 6,7 Tocilizumab is a recombinant humanized monoclonal antibody against IL-6 receptors. It is used for the treatment of a variety of diseases such as rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome in patients treated with T-cell engaging therapies. [8][9][10] Initial data from China reported the resolution of pyrexia, decreased oxygen requirements, improved radiologic findings, and reduced inflammatory markers by day 5 after therapy with tocilizumab. 11 There are publications about the impact of tocilizumab on COVID-19 that included descriptive and randomized control trials. [12][13][14] The purpose of this study was to evaluate the effect of tocilizumab therapy on the clinical outcomes of COVID-19 patients.

Study Population
We conducted a single-center, retrospective, observational cohort study at the New York City Health + Hospitals/Queens, an inner-city, safety-net community teaching hospital in New York City. Patients with a laboratory-confirmed positive SARS-CoV-2 nasopharyngeal swab via polymerase chain reaction test admitted between March 1, 2020, and April 22, 2020, were screened for their inclusion in the study. The control cohort consisted of patients admitted before April 3, 2020, when tocilizumab was not yet available at our facility. The standard of care-at this timeincluded supplemental oxygen, hydroxychloroquine, azithromycin, therapeutic anticoagulation, and glucocorticoids (ie, dexamethasone). On April 3, 2020, off-label tocilizumab was offered in addition to the standard of care to treat COVID-19 patients who met institution-specific eligibility criteria (e-Eligibility in Supplement 1, http://links.lww.com/IDCP/A44). The respiratory disease severity, an ordinal scale, was developed based on oxygen requirements, mode of oxygen delivery, and mechanical ventilation (MV). It included 5 categories: 0 (no oxygen requirement), 1 (oxygen delivery via nasal cannula for saturation less than 94%), 2 (oxygen delivery via nonrebreather/OxyMask), 3 (oxygen delivery via noninvasive MV), and 4 (invasive MV; e-Methods in Supplement 1, http:// links.lww.com/IDCP/A44).
Patients were excluded from the study if they had a contraindication to tocilizumab, 15 expired within 48 hours of admission, or were transferred to another facility without a unified electronic medical record.
The tocilizumab group was randomized in a 1:2 ratio to the control cohort adjusted for age and sex (Fig. 1). The Icahn School of Medicine at Mount Sinai and the New York City Health and Hospitals/Queens Institutional Review Board approved this study after obtaining a waiver for informed consent.

Tocilizumab Treatment
The tocilizumab treatment group received an intravenous dose of tocilizumab 400 mg with an optional second dose of 400 mg or 8 mg/kg weight-based dose 12 hours later. The tocilizumab and control groups received the standard of care, including optimal treatment with supplemental oxygen if oxygen saturation was less than 94% on room air. The standard therapy included hydroxychloroquine 16 with a loading dose of 400 mg twice daily for the first day followed by 200 mg twice daily for the remaining 4 days, azithromycin with a loading dose of 500 mg followed by 250 mg daily for a total of 5 days, anticoagulation, 17 and systemic corticosteroids. 16,18,19 Outcomes The primary outcome was COVID-19-related in-hospital mortality, whereas the secondary outcomes included the requirement of invasive MV, severity of respiratory disease, hospital length of stay (LOS), intensive care unit (ICU), and safety outcomes. The safety outcomes included anaphylaxis, injection site reactions, increased serum transaminases greater than 3-folds (the normal upper limit), and a positive QuantiFERON test. The commonly reported COVID-19 complications, including acute stroke, thromboembolic events, and atrial fibrillation with a rapid ventricular response, were categorically recorded. The thromboembolic events were further evaluated in the context of IL-6 elevations for the patients on tocilizumab therapy. The authors also compared thromboembolic events with deaths and IL-6 levels of the tocilizumab group patients.

Statistical Analysis
The continuous data were first assessed for normality using the Shapiro-Wilk test. In all cases, the outcome was negative, and thus, nonparametric tests were used to assess continuous numeric data. Next, the dichotomous outcomes were analyzed with Fisher exact test. The multivariate logistic regression analyses were performed using the variables (outlined in Table 1) with survival as the dependent attribute. The nonsignificant variables were removed in a backward stepwise process until only significant variables remained in the model. The survival analysis (time to event) was performed to produce Kaplan-Meier curves using as the "event." The data were censored for those patients who survived or whose outcomes were unknown after hospital discharge. All statistical analyses were performed with SAS Studio and JMP software (Cary, NC). The authors developed stacked bar charts for biologically analyzing the patterns of IL-6 levels, thromboembolic events, and deaths among patients with tocilizumab therapy. They also evaluated the variations in the C-reactive protein (CRP) levels of tocilizumab therapy patients with thromboembolic events.

RESULTS
After applying exclusion criteria, 150 patients treated with tocilizumab and 225 control patients were included in the study analysis. The demographic and baseline characteristics are described in Table 2. The median age was 62.5 years (interquartile range [IQR], 53-71 years) for the tocilizumab group and 64 years (54-73 years) for the control group. The tocilizumab group had fewer observed medical comorbidities compared with the control group, significant for congestive heart failure (2.7% vs 10.7%, P < 0.005), diabetes mellitus (38.7% vs 51.1%, P = 0.02), and smoking history (2.0% and 10.2%, P < 0.005). The overall body mass index (BMI) was similar in both groups.

Primary Outcomes
The COVID-19 management through tocilizumab reduced the incidence of in-hospital mortality compared with the control group. The logistic regression analysis revealed a 25.3% incidence of in-hospital mortality in patients who received tocilizumab compared with 46.7% in the control group ( P = 0.0136).

Secondary Outcomes
The treatment with tocilizumab led to a significant decrease in the MV requirement for treatment group compared with the control group after day 1 ( P = 0.0005), day 3 ( P < 0.0001), and day 5 ( P = 0.002). The tocilizumab group experienced a longer median hospital LOS (10 vs 7 days, P = 0.0002, Mann-Whitney). There were no observed differences in ICU LOS (9 vs 6 days, P = 0.079) or duration of MV (8 vs 5.5 days, P = 0.442). There was a transient increase of liver enzymes up to 3-fold in 22 of the tocilizumab-treated patients within 5 days after treatment. No anaphylactic or injection site reactions were reported.

LOGISTIC REGRESSION ANALYSES
The logistic regression analyses show that P values, odds ratios, and their 95% confidence intervals (CIs) are summarized in Table 1. For the entire cohort of 375 patients, the blood oxygen saturation level was the strongest predictor of survival ( P < 0.001). This remained true for the group not treated with tocilizumab ( P < 0.001). The age was also a strong predictor ( P = 0.019) for the entire population; however, within the tocilizumab group analyses, age ( P = 0.007) surpassed the blood oxygen saturation level ( P = 0.010) as a significant predictor of survival. The BMI was not a significant predictor of survival in any of the study groups. Asthma was a predictive factor of survival for the entire cohort (odds ratio [OR] = 2.61, 95% confidence interval [CI] = 1.11-6.12, P = 0.022) including the tocilizumab group (OR, 11.00; 95% CI, 1.89-64.0, P = 0.004).
The optimal timing for predicting survival was further analyzed in 3 separate regression analyses using different administration windows. Tocilizumab therapy within the first 48 hours of patient admission was found to be a significant predictor of survival (OR, 3.86; 95% CI, 1.38-10.8; P = 0.010); however, no correlation between tocilizumab therapy and survival rate was found within 48 hours ( P = 0.388) or 72-hour administration window ( P = 0.448).
The Kaplan-Meier curves display the results of survival analysis for both study groups (Fig. 2). The findings revealed a statistically significant difference supported by the log-rank test ( P = 0.009) and the Wilcoxon test ( P = < 0.001).
A downtrend in CRP marker within 5 days was observed among 81 patients (54%) receiving tocilizumab versus 15 control patients (6.6%) based on at least 2 values. The incomplete CRP data with 1 value or less within 5 days from treatment was 60 (40%) in the tocilizumab group compared with 201 (89.3%) in the control group. This outcome was investigated further using a  AKI, acute kidney injury (defined as serum creatinine >1.5 times higher than the baseline or increase of 0.3 mg/dL); ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; INR, international normalized ratio; LDH, lactate dehydrogenase; O 2 , oxygen; WBC, white blood cells. group analysis of matched pairs with a subset of data where CRP levels were available for all 3 time points (1, 3, and 5 days) after initiating treatment with tocilizumab or standard of care. These data were available for 16 patients undergoing treatment with tocilizumab and for 9 patients from the control group. Although the mean differences in CRP values between days 3 and 1, days 5 and 1, and days 5 and 3 within the pairs were not significantly different between the groups ( P = 0.583, 0.467, and 0.114, respectively), the mean of means was significantly lower for the tocilizumab group ( P = 0.002, 0.001, and <0.001).
The data review further revealed the administration of convalescent plasma to 13 patients (8.6%) from the tocilizumab group and 3 patients (1.3%) in the control group. Six patients (3.6%) from the tocilizumab-treated group and none from the control group received remdesivir therapy. These data were not included in the analysis considering the lower number of patients and the risk of confounded outcomes.

Biological Analysis
The Pattern of IL-6 Levels in 13 Patients in the Tocilizumab Group The results did not confirm a clinical correlation between IL-6 levels, thromboembolic events, and tocilizumab therapy. Two patients on tocilizumab therapy developed thromboembolic events on day 5 of their hospital admission (Fig. 3). Their IL-6 levels were recorded as 2822.6 and 3000 pg/mL, respectively. The IL-6 levels of 5 (tocilizumab therapy) patients with thromboembolic events ranged between 77 and 810.4 pg/m on day 3 of their treatment. The IL-6 levels of 2 patients with thromboembolic events were recorded as 41.7 and 241.5 pg/mL on day 1 of their tocilizumab therapy. Six patients on tocilizumab therapy developed thromboembolic episodes, whereas their IL-6 levels ranged between 37.6 and 105.8 pg/mL on day 0 of their treatment. Twelve patients with thromboembolism (and selected for tocilizumab therapy) had IL-6 levels between 19.7 and 2180.6 pg/mL on the day of their hospital admission (Fig. 3). The findings did not reveal a marked elevation in the IL-6 levels of tocilizumab therapy patients until day 5 of their medical management. The patient data did not reveal a statistically significant correlation between the IL-6 levels of tocilizumab therapy patients and thromboembolic events.

Comparison Between Thromboembolic Events Versus Deaths Versus IL-6 Levels of Patients on Tocilizumab Therapy
Nine of 13 patients who received tocilizumab therapy and developed thromboembolic events could not survive coronavirus disease and died before hospital discharge. The IL-6 levels of these patients ranged between 19.7 and 2822.6 pg/mL, respectively. The deterministic factors of their death from thromboembolism warrant further investigation. The limited patient data restricted the comparative analysis between mortality, thromboembolic episodes, and IL-6 levels of the tocilizumab therapy patients. The assessment of the physiological mechanisms dominating the IL-6 elevation in the tocilizumab therapy patients is out of the scope of this study.

Oxygen Requirements for Mechanically Ventilated Patients on Tocilizumab With Corticosteroid Therapies
The oxygen requirements for the mechanically ventilated patients on tocilizumab and corticosteroid therapies varied considerably between 0.6% and 100% until day 5 of their treatment. The high oxygen demand for a few mechanically ventilated patients compared with low-to-moderate oxygen requirements of other patients on MV did not clinically correlate with the administration of tocilizumab and corticosteroid therapies. The study did not examine external (environmental) or biological (internal) factors impacting the need for MVamong patients who concomitantly received tocilizumab and corticosteroid therapies.

C-Reactive Protein Levels of Tocilizumab Therapy Patients With Thromboembolic Events
The study data revealed a marked reduction in the CRP levels of the tocilizumab therapy patients from the date of their admission to the fifth day of treatment. The CRP levels of the tocilizumab therapy patients with thromboembolic events ranged between 93.80 and 300 mg/L; however, their CRP levels dropped to 2.90 to 187.50 mg/L on day 5 of their treatment. These findings, however, lacked clinical relevance because of the smaller sample size for thromboembolic events in the context of tocilizumab therapy.

DISCUSSION
In this study of 375 hospitalized patients with COVID-19 disease, treatment with tocilizumab was associated with reduced in-hospital mortality. In addition, the need for MV on days 1, 3, and 5 post-COVID-19 treatment was significantly lower in the tocilizumab group. The severity of COVID-19 disease is postulated to be partially driven by hyperactive inflammation and cytokine release syndrome as evidenced by elevated biomarkers, such as serum IL-6 and CRP. 4 If left untreated, systemic inflammation leads to hemodynamic instability, multiorgan failure, microvascular thrombosis, and mortality. 20 Several studies have found a beneficial effect of the IL-6 inhibitor tocilizumab in modulating the hyperactivated immune response of the COVID-19 patients. 7,11,19,21,22 The results of our study are consistent with the association of tocilizumab with a statistically significant decrease in mortality.
The timing of tocilizumab administration may have an impact on its overall safety and efficacy. The association of tocilizumab administration within the first 48 hours lowered the inhospital mortality in our study in concordance with the findings of Gupta et al 22 (2020). The early administration of tocilizumab may benefit COVID-19 patients by attenuating their inflammatory responses mitigating their end-organ damage. 8,19,21 The initial IL-6 values were lower in the tocilizumab group compared with the control group (a median of 76.1 vs 142, P = 0.01); however, these values may not accurately depict the true IL-6 levels in our control group as only 8% of patients had a documented IL-6 level compared with 96.3% of patients in the treatment group. Nonetheless, the median IL-6 levels reported in our study are similar to the previously reported IL-6 levels in COVID-19 patients, which remain lower than the mean peak IL-6 levels in comparative disorders, such as acute respiratory distress syndrome and sepsis. 3 The dose of tocilizumab administered was 400 mg in most patients reviewed for this study, with only 6 patients receiving a second dose. This intervention occurred before implementing our institution-specific guidelines concerning the use of weightbased dosing (of 8 mg/kg up to a maximum of 800 mg) with an optional second dose administered 12 hours later. 23 In critically ill patients, the second dose of tocilizumab is recommended to achieve adequate therapeutic levels. 19,24 Toniati et al 19 (2020) used 2 consecutive intravenous doses of 8 mg/kg (maximum, 800 mg) 12 hours apart and reported significant clinical improvement among COVID-19 patients. 19 Additional studies are warranted to investigate the optimal dosing and frequency of tocilizumab in the setting of COVID-19.
The concomitant therapeutic anticoagulation and corticosteroid use in our study was found to decrease the overall survival of the COVID-19 patients. The patients who received therapeutic anticoagulation were more likely to have a higher disease severity as evidenced by elevated D-dimer and proinflammatory biomarkers compared with those who only received prophylactic dosing. The tocilizumab group had more thromboembolic events than the control group (13 [7.9%] vs 9 [4%], P = 0.07); however, this finding seems contradictory, given the established procoagulant effect of IL-6 and the demonstrated decrease in factor XIII and prothrombin fragments with tocilizumab. 25,26 The overall incidence of thromboembolic events may not hold reliability during the study tenure because of the limitation in radiologic studies based on the risk of secondary infection.
The data on corticosteroid use for COVID-19 patients are inconclusive in the medical literature. 26 The RECOVERY trial reported a decrease in 28-day mortality in patients receiving dexamethasone and requiring supplemental oxygen or invasive MV. 18 The use of glucocorticoids (ie, dexamethasone) was found to be a significant predictor of survival in both the treatment and control groups. However, similar to the patients receiving therapeutic anticoagulation, the decreased odds of survival may likely be a representation of higher severity of illness in those patients selected to receive glucocorticoids (ie, dexamethasone) during the pandemic.
Contrary to expectations, asthmatic patients have a lower global prevalence of COVID-19. 27,28 Our results show that the presence of asthma was an independent predictor of survival of COVID-19 patients. This finding could be explained by the type 2 immune responses involving several cytokines leading to the protective effects of eosinophil accumulation. 28 The angiotensinconverting enzyme 2 receptors are responsible for anchoring the spike proteins of SARS-CoV-2, while transmembrane protease serine 2 cleaves the spike protein after invading the cells. The reduced expression of these 2 receptors in the airway mucosa of asthmatic patients is attributed to their immunocompromised status, type II allergic inflammation, and comorbidities. 27,29 In addition, the patients with asthma might have presented earlier to receive medical care and started on systemic corticosteroids at the early stages of their disease, which might be beneficial. 18 Our findings are consistent with several retrospective studies suggesting the reduction in MV and mortality after tocilizumab administration, as described by Guaraldi et al 30 (2020). Another case-control study originating from France shows a reduction in ICU admissions and deaths among patients hospitalized with COVID-19. 31 Similar data from a multicenter observational study by Biran et al 32 (2020) support the mortality reduction potential of tocilizumab for ICU patients admitted with SARS-CoV-2 pneumonia. In addition, the patients who received tocilizumab had a decreased requirement for vasopressors compared with control. 33 The STOP-COVID study demonstrated a lower risk of inhospitality mortality in critically ill patients treated with tocilizumab within the first 2 days of their ICU admission. 22 The available data from randomized clinical trials report conflicting outcomes concerning the therapeutic benefits of tocilizumab therapy. The COVACTA study, a phase III randomized clinical trial, failed to show a reduction in mortality or clinical status improvement after tocilizumab use for 4 weeks. A decrease in the hospital LOS in the tocilizumab cohort was reported yet deemed insignificant as the primary endpoints were not met. 34 Sarilumab, another IL-6 inhibitor, also failed to improve the clinical outcomes across patients on MV after 28 days of hospitalization. 35,36 The CORIMUNO randomized clinical trial met its composite primary end point of reducing the need for ventilation (either noninvasive or invasive) and mortality within 14 days of hospitalization for moderate-to-severe pneumonia. 37 The most recent data from the IMPACT phase III study showed that hospitalized patients who received tocilizumab were 44% less likely to require MV compared with the placebo group. The study findings by Salama et al 34 proved statistically insignificant concerning the mortality benefit. The Boston Area COVID-19 Consortium study, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, did not reveal any improvement in MV, clinical course, or mortality until the 28th day of treatment in the setting of COVID-19. 38 Veiga et al 39 (2019), a small randomized controlled clinical trial, did not advocate any benefit in clinical outcomes at 15 days by administering tocilizumab therapy to the critically ill COVID-19 patients. The findings contrarily reported an increase in the mortality rate among the treated patients. The findings of these studies were potentially restricted by their methodology, lack of blinding, insufficient power, and ethnically diverse populations. Recently, the RECOVERY trial demonstrated the therapeutic efficacy of tocilizumab therapy in improving the survival rate and other clinical outcomes among COVID-19 patients with hypoxia and systemic inflammation. These benefits increased reciprocally with the concomitant use of systemic corticosteroids. 40 The findings of this study did not confirm a linear correlation between IL-6 level elevation and tocilizumab therapy for COVID-19 patients with thromboembolic events. Our study also did not provide concrete evidence concerning the reduction in IL-6 levels after the administration of tocilizumab to the COVID-19 patients. This finding contradicts the systematic review by Kaye and Siegel 41 (2020) that confirmed the posttreatment benefits of tocilizumab therapy for COVID-19 patients (in terms of) reducing their lymphocytes, neutrophils, CRP, and IL-6 levels. The case study by Michot et al 42 (2020) confirmed the safety and efficacy of the anti-IL-6 receptor antibody (tocilizumab) in terms of minimizing the risk of respiratory failure in COVID-19 patients. The study also confirmed the IL-6 reduction potential of tocilizumab for immunocompromised COVID-19 patients. 42 The scientific review by Zhang et al 35 (2020) advocated the IL-6 signal transduction pathway blockade by tocilizumab. Future studies should accordingly investigate the IL-6 receptor blockade potential of tocilizumab therapy in the context of restricting the classical IL-6 signal in critically ill COVID-19 patients.
This study did not find credible evidence concerning the clinical correlation between thromboembolic events, IL-6 levels, and deaths among patients on tocilizumab therapy. The systematic review and meta-analysis by Pinzon et al 36 (2021) revealed a strong relationship between IL-6 inhibitor drugs and mortality reduction in the setting of COVID-19. The findings also revealed the potential of IL-6 inhibitors (including tocilizumab) to minimize the length of hospital stay and MV requirements among the COVID-19 patients on tocilizumab therapy. A retrospective study by Castelnovo et al 43 (2021) confirmed the efficacy of tocilizumab in improving the prognostic outcomes of critically ill COVID-19 patients. The findings further revealed the systemic benefits of tocilizumab concerning the reduction in microvascular complications, inflammatory levels, multiorgan failure, and mortality rate in the setting of COVID-19. Another retrospective study by De Rossi et al 44 (2021) indicated the therapeutic benefits of tocilizumab in minimizing excessive hyper inflammation and mortality rate for COVID-19 patients with pneumonia. The results of a case series by Atallah et al 45 (2020) contrarily revealed an elevation in the thromboembolic events in the setting of COVID-19 despite the use of anticoagulation tocilizumab therapy and a reduction in inflammatory markers. The retrospective study by Capra et al 21 (2020) revealed the enhancement in the clinical course and survival rate among the COVID-19 patients after the administration of low-dose tocilizumab. The findings suggested the early use of tocilizumab therapy to effectively improve the COVID-19 prognosis and recovery of the patients with a high risk of the severe acute respiratory syndrome. The current body of evidence does not elaborate on the mechanisms dominating the IL-6 blockade effects of tocilizumab and its potential to inhibit the activity of vascular endothelial cells and coagulation pathways. 6 These contradictions form a strong baseline for future studies warranted to expand current evidence concerning the role of tocilizumab therapy in controlling the mortality rate among COVID-19 patients by reducing their predisposition to IL-6 elevation and thromboembolic episodes.
The findings of our study revealed a marked variation in the oxygen requirements of the mechanically ventilated COVID-19 patients on tocilizumab therapy. The observational study by Di Nisio et al 46 (2021) supported the potential of tocilizumab therapy in reducing the tissue oxygen demand and elevating the oxygen saturation levels in critically ill COVID-19 patients. The case study by Papamichalis et al 47 (2020) confirmed the therapeutic benefits of administering tocilizumab with recombinant tissue plasminogen activator in minimizing the respiratory complications of COVID-19 patients. A multicenter retrospective study by Tomasiewicz et al 48 (2020) affirmed the therapeutic benefit of tocilizumab in terms of minimizing the need for COT (continuous oxygen therapy) for COVID-19 patients within a week of their treatment. The rise in the oxygen saturation levels of the critically ill COVID-19 patients from 90% to 100% within 10 days of the first dose of tocilizumab indicates the potential of this drug to enhance the clinical status and minimize the inflammatory response of the patients with COVID-19. These results substantiate the requirement of future studies to investigate the role of tocilizumab in minimizing the tissue oxygen demand or elevating the oxygen saturation levels of the COVID-19 patients.
Our study provided evidence concerning the reduction in CRP levels of the COVID-19 patients after the administration of tocilizumab therapy. This finding concords with the outcomes of an observational study by Price et al 49 (2020) that confirmed the potential of tocilizumab therapy in minimizing the inflammatory processes of cytokine release syndrome-related inflammatory mechanisms by reducing the high-sensitivity C-reactive protein levels in COVID-19 patients. Another single-center experience study by Luo et al 50 (2020) reported a reduction in CRP levels and subsequent clinical stabilization in COVID-19 patients on tocilizumab therapy. These results strengthen the current evidence concerning the CRP reduction potential of tocilizumab.

Limitations
Our study has several limitations that we unequivocally acknowledge. As an observational single-center study, we cannot make any causal inference based on our results and findings that may have been limited because of the incomplete documentation of COVID-19 treatment scenarios in the electronic medical records. The sample size is relatively small. The baseline demographics in both groups were similar for age, sex, and BMI, whereas the race distribution and comorbidities were heterogeneous within the selected groups (with tocilizumab-treated patients having fewer observed chronic medical problems). These differences may have been the result (of selection bias) secondary to the frequency matching used to form the control group. In addition, the statistically significant finding regarding the potential of tocilizumab in controlling the CRP levels holds limited value because this result corresponded to a small section of patients.

CONCLUSIONS
Tocilizumab therapy within 48 hours of admission for the management of COVID-19 reduced the in-hospital mortality and the need for MV. The large sample prospective studies should further investigate the utility, dosage, and timing of tocilizumab for COVID-19 patients. There is a need to determine the potential of tocilizumab monotherapy (excluding corticosteroid treatment) in improving the clinical outcomes, prognosis, and recovery of critically ill patients with COVID-19.