1. IntroductionThe coronavirus SARS-CoV-2 has been at the center of a worldwide pandemic that has plagued the world since December 2019 [1,2]. Patients infected with COVID-19 have a 75% chance of completing their recovery without major complications, but a 25% probability that they may become critically ill and require intensive care unit (ICU) treatment or even ending with death [3]. COVID-19 can cause a wide variety of symptoms and signs, from no symptoms at all to life-threatening pneumonia and respiratory failure causing acute respiratory distress syndrome (ARDS), leading to a high need for supplemental oxygen. It is possible for the disease to progress from its first phase of viral replication into a second phase driven by the host inflammatory response, resulting in the rapid onset of severe respiratory failure. Typical radiological data implies that infection with coronavirus 2 (SARS-CoV-2) may trigger a hyperimmune response associated with acute respiratory distress syndrome. Patients in the worst shape can experience something called a “cytokine release storm” [4].Cytokine release syndrome (CRS) has been reported to cause COVID-19 related morbidity and mortality. CRS is due to the excess release of proinflammatory cytokines, especially Interleukin-6 (IL-6) [5]. IL-6 causes respiratory dysfunction including severe alveolar damage, alveolar-capillary leakage, and impaired blood–gas exchange (especially oxygen diffusion) [6]. Recent IL-6 antagonists, especially tocilizumab, have been repurposed for the remission of CRS in COVID-19 patients as adjunctive therapy where multiple case series have suggested a potential role for tocilizumab.Tocilizumab (TCZ) is a monoclonal antibody against the IL-6 receptor that has found widespread application in the treatment of rheumatic illnesses and severe Chimeric Antigen Receptor (CAR) T cell-induced CRS around the world. Treatment of critically ill patients with COVID-19 may benefit from TCZ because of its potent influence on the inflammatory response brought on by the virus. However, it is important to use TCZ at the right points in the treatment plan [7].There was large variation in the results of the previous studies that range from effect on mortality, time to clinical improvement, and prevention of progression to a more severe form of the disease [8]. This indicates that the standardization of the tocilizumab dose or the stage of the disease at which the drug is administered have not been well established, as well as the type of patients that will benefit from this drug. Other factors that may contribute in the pathophysiology of the disease are the patient’s characteristics and the presence of different SARS-CoV-2 strains [9]. By providing an estimate of the immunomodulatory agent’s possible effects, and for the high cost of tocilizumab, which in turn may be a burden on the healthcare system, observational studies may aid in the design of randomized clinical trials for the remission of critically-ill COVID-19 patients [10]. Thus, we aim to assess the efficacy of tocilizumab in the remission of COVID-19 patients hospitalized in the ICU. We also aim to assess the effect of tocilizumab on the length of the hospital stays and the result of co-administration of tocilizumab with other treatments. 2. Methods 2.1. Study Design and Seting

From January 2021 to June 2021, a multi-center retrospective cohort study was conducted on the intensive care units of six hospitals in Giza Governorate, Egypt. Among these, Al Tahrir, Om Elmasryeen, and Al Hawamdyia are the three General Hospitals, and the Central Hospitals include Al Warraq, Six of October, and Elsheikh Zayed. The Declaration of Helsinki and World Health Organization recommendations were all adhered to throughout the current study. The research protocol has been reviewed and approved by the “Research Ethics Committee” of the Central Directorate for Research and Health Development in MOHP (REC No. 23-2021/14).

2.2. Subjects

The study included all patients with a diagnosis of moderate to severe COVID-19 pneumonia who were admitted to the intensive care units of Giza hospitals. The study excluded patients with mild COVID-19, patients under the age of 18, patients who died within 48 h of being admitted, pregnant women, patients who were breastfeeding, and patients with mild COVID-19 symptoms.

2.3. Sampling Technique and Method of Selection

Consecutive sampling techniques were applied. Certain hospitals in Giza Governorate were selected to collect data from the patient records. All patients of each hospital who fulfilled the inclusion criteria were chosen. Data of 112 tocilizumab administrated patients were collected, and 2 of them were excluded for not fulfilling the criteria. On the other hand, 1257 data records were obtained from patients who were taking the routine protocol. Only 630 were included in the study, which was due to duplication of entry, entry errors, not fulfilling inclusion criteria, and incomplete data records.

2.4. Data Collection Tools

We used a predesigned structured questionnaire to collect the following data from the hospitals. The questionnaire was organized as follows: (Form A) covered patient identifiers, age, sex, coexisting conditions, investigations performed at the time of admission, treatments received in the hospitals and patients’ outcomes. (Form B) covered TCZ-related conditions: Criteria of severity of COVID-19 associated cytokine storm syndrome, contraindication, and side effects of TCZ.

2.5. Treatment Protocol and Outcomes

COVID-19 patients were tested using a COVID-19 laboratory panel consisting of C-reactive protein (CRP), ferritin, d-dimer, lactate dehydrogenase, and troponin I, as per institutional procedure. Tocilizumab treatment was given to patients who met the following requirements: symptoms of respiratory compromise including tachypnea, dyspnea, OR peripheral capillary oxygen saturation (SpO2) 90% on at least 4 L of oxygen OR rising oxygen requirements over 24 h, PLUS 2 or more of the following predictors for severe disease: C-reactive protein level higher than 35 mg/L, a ferritin level over 500 ng/mL, a D-dimer level over 1 mcg/L, a neutrophil-lymphocyte ratio over 4, or a lactate dehydrogenase level over 200 U/L.

All patients received a single IV infusion of 400 mg of tocilizumab as part of the therapy protocol. After tocilizumab delivery, antimicrobial prophylaxis was not consistently administered [11]. The patients’ clinical status was evaluated as the main outcomes, including being alive at discharge and death rate, and the secondary outcome including time to hospital discharge and predictors of mortality were also analyzed in the study. 2.6. Statistical Analysis

Data management and statistical analysis were performed using the Statistical Package for Social Sciences (SPSS) version 24(SPSS Inc, Chicago, IL). After being checked for accuracy, the obtained data were recoded, entered into a database, and statistically evaluated using the proper statistical tools and tests. Means, standard deviations, or medians and ranges were used to summarize numerical data. The Shapiro–Wilk test and Kolmogorov–Smirnov test were used to determine the data normality. Percentages were used to summarize categorical data. In quantitative variables, comparisons between patient groups were made using the independent t-test. Fisher’s exact tests and χ2 (chi square) tests were used to assess differences for categorical variables. A multivariate logistic regression was used to evaluate factors affecting primary outcomes. Kaplan–Meier curve and log rank test were used for survival analysis. p-values are always two-sided. p-values below 0.05 were deemed significant, and the Bonferroni technique was used to account for multiplicity.

4. DiscussionCytokine storm was thought to be a significant factor in COVID-19 exacerbation and even death, since it can cause immunological dysregulation, lung tissue damage, hypoxia, and even respiratory failure [12,13]. Tocilizumab was reported to regulate the cytokine storm and inflammation in COVID-19 [14,15].Even though our study did not find any advantages of tocilizumab over the conventional treatment in terms of mortality or length of hospital stay, other observational studies have shown better outcomes. The two largest observational studies to date on this topic have demonstrated an association between tocilizumab use and decreased mortality [16,17]. Guaraldi et al. evaluated the impact of tocilizumab regardless of the time of administration on a cohort of 1351 COVID-19 patients [16]. However, invasive ventilation or death was the composite endpoint, and patients admitted to the intensive care unit were not included. In the STOP-COVID tocilizumab study, which comprised 3924 severely ill COVID-19 patients admitted to ICUs, patients who received tocilizumab within the first two days of admission had a lower mortality risk than those who did not get tocilizumab within the first two days of admission [17]. In contrast to these two trials, the largest cohort study of 544 COVID-19 patients, carried out by Cardona-Pascual et al., supports our findings that tocilizumab treatment did not lower the risk of mortality in patients with moderate to severe COVID-19 [18]. However, ICU stay in tocilizumab group was found to be shorter than in the control group. In the observational studies stated above, different dosages (single or double) and subpopulations were investigated (moderate or severe or critically ill patients).

According to our knowledge, this study is the first large multicenter cohort observational study in Egypt to examine the role of tocilizumab in COVID-19 infection. We enrolled 740 COVID-19 patients, and the findings showed that there was no statistically significant difference in mortality between the tocilizumab group and the control group.

In particular, recent RCTs have not demonstrated a decrease in mortality in COVID-19 patients receiving tocilizumab [19,20,21]. Regardless of the time of administration, the number of tocilizumab doses administered, or the subset of critically ill patients admitted to the ICU, our results are consistent with those from the RCTs and demonstrate no benefit in the mortality in COVID-19 patients treated with tocilizumab. Our findings may also be consistent with earlier RCT and observational studies. A total of 51.7% of patients in the control group and 46.4% of those who received tocilizumab had been discharged from the hospital alive. Our discharge rate was similar to the study conducted by Somers et al. [22]. Indeed, we reported a high mortality rate of 53.6% compared to the control group, which is consistent with a prior study that assessed the association between tocilizumab and mortality in COVID-19 patients conducted by Campochiaro et al., who found no appreciable change in the mortality in tocilizumab-treated patients [23]. On the other hand, tocilizumab has been associated with a reduced risk of death and hospital-related mortality, according to a number of other studies [16,17,24,25,26,27,28,29].Overall, results from different studies on the mortality rate associated with tocilizumab treatment in COVID-19 patients are contradictory, most likely as a result of disparate study designs and clinical severity classification heterogeneity. It should be noted that comparisons between observational studies are challenging due to variations in baseline disease classification heterogeneity, participant clinical severity heterogeneity, non-standardized timing, dosage, and administration of tocilizumab, low statistical power resulting from a small participant pool, lack of standardized care in the control groups, and a lack of corticosteroid effect evaluation [30]. Indeed, we contrasted the respiratory support that we offered to hospitalized patients at all participating hospitals between those who were discharged and those who sadly died. It was observed that non-rebreathing oxygen support devices, CPAP, and mechanical ventilation (MV) had the highest mortality rates compared to simple oxygen masks and nasal canula.The incidence of serious infections is the greatest concern with tocilizumab therapy [31]. In this study, patients in the tocilizumab group required a median hospital stay of 10 days compared to 8 days in the control group. This difference can be attributed to the secondary bacterial infections, which necessitate additional antibiotic medication and decrease patient oxygenation.

The multicenter design of this trial, careful data quality monitoring, and a homogeneous target population of patients with moderate and severe pneumonia are the strengths of the study.

6. Limitations

Even though we imputed missing data using modern techniques, the laboratory variables had some incomplete data. IL-6 serum concentrations were not frequently available; thus, this study did not evaluate their potential utility or how they might have predicted a patient’s response to tocilizumab.

Additionally, in the retrospective design of the research there were some possible confounders from the concomitant application of multiple interventions at the same time of TCZ administration. So, the results need confirmation by randomized controlled trials.