INTRODUCTION
Coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune response leading to a hyperinflammatory state, termed cytokine storm.[1-3] The disease severity depends on macrophage activation, which releases proinflammatory cytokines, subsequently causing an exaggerated host immune response leading to organ dysfunction.[4,5] Administering interleukin-6 (IL-6) receptor antagonists may reduce the progression of disease severity associated with COVID-19 pneumonia.[6] Recent trials have shown equivocal results in the drug’s efficacy concerning patient outcomes.[2,3,6] This prompted us to conduct a retrospective case–control study to evaluate the impact of tocilizumab on patients suffering from COVID-19. We present the following research in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting checklist.
METHODS
The Institutional Ethics Committee of the Institute of Medical Sciences (IMS) and SUM Hospital approved the study (vide approval number IEC/IMS.SH/IN-75/2022 dated 02.01.2023) with a waiver of informed consent. The data was collected from a tertiary care hospital in eastern India from March 2021 to July 2021 from electronic medical records (EMR). Any discrepancy in EMR was resolved by retrieving data from patient records in the medical records department. COVID-19 pneumonia was classified as mild, moderate and severe based on the clinical criteria and computed tomography (CT) chest criteria. The study was carried out in accordance with the principles of the Declaration of Helsinki, 2013.
Patients aged between 18 and 65 years with severe COVID-19 pneumonia (nasopharyngeal reverse transcription polymerase chain reaction [RT-PCR] positive for severe acute respiratory syndrome coronavirus 2 [SARS CoV-2]) and associated hyperinflammation (C-reactive protein [CRP] more than 75 mg/l) were included. Patients receiving immunomodulators, immunocompromised patients (solid organ transplant, uncontrolled diabetes with glycosylated haemoglobin [HbA1c] >8%, malignancy) and patients with elevated serum procalcitonin and positive blood cultures on admission were excluded. All patients received standard treatment per institutional protocol (intravenous dexamethasone 6 mg once a day [OD], subcutaneous enoxaparin 60 mg OD, oral vitamin C 500 mg twice daily). In addition, the study group received intravenous tocilizumab 400 mg and a second dose after 24 h. Key confounders were identified as sex, age, disease severity, and baseline simplified acute physiology score (SAPS)-II score. Based on these key confounders, a matched control group was included after minimising selection bias, and the control group received standard treatment.
The primary outcome was to assess the mortality benefit (if any) of the use of tocilizumab. The secondary outcome was to evaluate risk factors affecting the in-hospital mortality in patients who received tocilizumab and the effect of tocilizumab on oxygen requirement. Data on demographics, the severity of disease, SAPS-II, the fraction of inspired oxygen (FiO2) requirement and mode of oxygen delivery (non-rebreathing mask, high-flow nasal cannula, non-invasive ventilation and invasive mechanical ventilation) was collected on admission and day 7, day 14 and day 28, as appropriate. Adverse events such as pulmonary thrombosis and pneumothorax were recorded.
With anticipated mortality of 55% among COVID-19 patients who were on mechanical ventilation (as per the hospital monthly data during the COVID-19 pandemic) we expected decrease in mortality by 20% in the tocilizumab group. Based on the above assumption, the sample size was calculated to be 144 to provide a power of 80% and an alpha error of less than 5%. Continuous variables were expressed as the median and interquartile range (IQR) and compared by the Mann–Whitney U test. Categorical variables were expressed in percentages, and the Chi-square test was used to compare the groups. Fisher exact test was used to compare mortality between the two groups. A P value less than 0.05 was considered statistically significant. All statistical analyses were performed using the statistical package for social sciences (SPSS) software, v. 20.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
Out of 176 patients screened, 156 patients were included [Figure 1]; 52% were male, and 48% were female. The median duration of receiving tocilizumab, SAPS-II scores and Kigali ratios were comparable at baseline [Table 1]. Concerning our primary outcome, the tocilizumab group and the control group had a mortality of 50% and 66.6%, respectively (P = 0.023) [Table 1].
Figure 1.
Participant flow chart of the study
Table 1.
Comparison between tocilizumab group and control group
| All patient’s median (IQR) | Tocilizumab group median (IQR) | Control group median (IQR) | P | |
|---|---|---|---|---|
| Age (years) | 60 (46–68) | 57 (45–66) | 60 (46–69) | 0.265 |
| FiO2 (%) | 80 (60–90) | 80 (60–90) | 80 (60–90) | 0.544 |
| Serum PCT (ng/ml) | 0.29 (0.22–0.36) | 0.29 (0.22–0.36) | 0.29 (0.21–0.36) | 0.876 |
| CRP (mg/dl) | 90 (86–90) | 90 (86–90) | 90 (85–90) | 0.717 |
| SBP (mm Hg) | 130 (124–140) | 130 (125–140) | 130 (124–140) | 0.960 |
| HR (per min) | 86 (78–90) | 86 (78–90) | 86 (78–90) | 0.947 |
| RR (per min) | 26 (25–28) | 26 (24–28) | 27 (25–28) | 0.817 |
| SpO2 (%) | 94 (92–95) | 94 (92–95) | 94 (92–95) | 0.846 |
| Hb (g %) | 12 (11–13) | 12 (11–13) | 12 (11–13) | 0.939 |
| TLC (per mm3) | 9 (7–13) | 9 (7–13) | 8 (7–12) | 0.769 |
| TPC (per mm3) | 246 (189–301) | 246 (194–303) | 246 (184–303) | 0.781 |
| FiO2 on day 7 (%) | 70 (40–80) | 65 (40–80) | 70 (40–80) | 0.957 |
| FiO2 on day 14 (%) | 60 (21–90) | 40 (21–90) | 60 (21–90) | 0.432 |
| FiO2 on day 28 (%) | 21 (21–21) | 21 (21–21) | 21 (21–21) | 1.000 |
| Kigali ratio | 50 (25–75) | 118 (102–156) | 119 (103–156) | 0.526 |
| SAPS-II | 43 (38-49) | 43 (38–49) | 42 (34–50) | 0.625 |
| Mortality, n (%) | 92 (59%) | 39 (50%) | 53 (66.6%) | 0.023 |
CRP=C-reactive protein, FiO2=fraction of inspired oxygen, Hb=haemoglobin, HR=heart rate, IQR=interquartile range, PCT=procalcitonin, RR=respiratory rate, SAPS-II=simplified acute physiology score II, SBP=systolic blood pressure, SpO2=oxygen saturation, TLC=total leucocyte count, TPC=total platelet count. All values are expressed as median (IQR) unless otherwise noted
Regarding our secondary outcomes, when comparing survivors and non-survivors in the tocilizumab group, the median SAPS-II scores were 38 (IQR: 38–43) and 46 (IQR: 42–49), respectively, with a P value of <0.01 [Table 2]. Logistic regression was performed to find predictors for survivors versus non-survivors. Only the SAPS-II score could add significantly to the prediction (P = 0.003) with an odds ratio (OR) of 1.34 (95% confidence interval: 1.10, 1.62). No difference was observed between the groups in oxygenation on day 7, day 14 and day 28 [Table 1]. One patient in the tocilizumab group and two in the control group had pneumothorax. Three patients in the tocilizumab group had thrombotic events.
Table 2.
Comparison between survivors and non-survivors from the tocilizumab group
| Survivors median (IQR) | Non-survivors median (IQR) | P | |
|---|---|---|---|
| Age (years) | 55 (42–65) | 60 (46–70) | 0.199 |
| Serum PCT (ng/ml) | 0.29 (0.23–0.37) | 0.29 (0.22–0.36) | 0.936 |
| CRP (mg/dl) | 90 (88–90) | 90 (85–90) | 0.987 |
| SBP (mm Hg) | 130 (128–138) | 134 (124–140) | 0.205 |
| HR (per min) | 88 (78–90) | 86 (78–89) | 0.324 |
| RR (per min) | 26 (24–28) | 28 (26–30) | 0.054 |
| SpO2 (%) | 94 (92–96) | 93 (91–94) | 0.011 |
| Hb (g %) | 12 (11–14) | 12 (10–13) | 0.092 |
| TLC (per mm3) | 9 (7–13) | 9.40 (7.13–13.65) | 0.948 |
| TPC (per mm3) | 257 (191–324) | 242 (196–280) | 0.506 |
| SAPS-II | 18 (18–23) | 26 (22–29) | <0.0001 |
| FiO2 on day 7 (%) | 40 (30–50) | 80 (80–90) | <0.0001 |
| FiO2 on day 14 (%) | 21 (21–21) | 90 (80–97) | <0.0001 |
| FiO2 on day 28 (%) | 21 (21–21) | - | - |
| Kigali ratio | 122 (102–160) | 115 (102–134) | 0.162 |
| SAPS-II score | 38 (38–43) | 46 (42–49) | <0.0001 |
All values are expressed as median (IQR) unless otherwise noted. CRP=C-reactive protein, FiO2=fraction of inspired oxygen, Hb=haemoglobin, HR=heart rate, IQR=interquartile range, PCT=procalcitonin, RR=respiratory rate, SAPS-II=simplified acute physiology score II, SBP=systolic blood pressure, SpO2=oxygen saturation, TLC=total leucocyte count, TPC=total platelet count
DISCUSSION
In this retrospective case–control study, tocilizumab improved mortality in patients with equivalent SAPS-II scores. The early landmark trials conducted on tocilizumab, like the Boston Area COVID-19 Consortium (BACC) trial and the CORUMINO TOCI-1 trial, showed no mortality benefit from using tocilizumab.[7,8] Later on, interestingly, the Evaluating Minority Patients with Actemra (EMPACTA) trial showed that tocilizumab prevents progression to mechanical ventilation but without any mortality benefit.[2]
Previous investigators reported 28.0% and 35.8% mortality with tocilizumab and sarilumab, respectively, compared to usual care.[9] The researchers defined respiratory organ support as high-flow nasal oxygenation of more than 30 l/min and FiO2 demand of more than 0.4.[9] The tocilizumab group had a significant mortality benefit (50.0% vs 66.0%), consistent with the above studies. Death was higher because our research groups contained sicker patients in a cytokine storm. An increase of IL-6 levels occurs as an acute phase response to the disease process. As tocilizumab is an IL-6 receptor antagonist, we did not measure IL-6 levels. Interestingly, tocilizumab group patients had elevated IL-6 levels.[6] IL-6 levels have been used along with CRP to anticipate poor outcomes but not as a guide for tocilizumab therapy. [1,7,9]
An observational cohort analysis by Tinyan Hu et al. demonstrated that the SAPS-II score predicted 30-day death in non–COVID-19 intensive care patients better than our study.[10] Lower SAPS-II scores reflect a less-sick patient population. This subset of patients probably benefits the most from the usage of tocilizumab.
The December 2022 COVID-19 outbreak in China and the emergence of new variants require a re-evaluation of the virus-treating drugs. The main strength of this study is that it recorded tocilizumab’s safety and the adverse event data well. This study has limitations. First, this is a single-centre study conducted in a tertiary care teaching hospital. Second, being a retrospective study, it has confounding bias. However, considering the overwhelming nature of the COVID-19 pandemic on the healthcare systems, it could have been more pragmatic on our part to conduct a multicentre, prospective study. Future studies should evaluate the early usage of tocilizumab in COVID-19 with an emphasis on inflammatory markers.
CONCLUSION
Tocilizumab showed mortality benefits in severe COVID-19 pneumonia patients. Patients with higher SAPS-II scores in the tocilizumab group had a higher mortality rate. Therefore, early usage of tocilizumab in severe COVID-19 pneumonia patients may be beneficial.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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