We found a significant reduction in risk of death in severe COVID-19 pneumonia with persistent hypoxia receiving a single dose of intravenous tocilizumab 400mg, compared with those treated with standard care alone. The hazards of dying in the tocilizumab group were 0.621 times of that in the control group. We reported 47.1% mortality in our first 70 patients of severe COVID-19 pneumonia with persistent hypoxia treated with tocilizumab till 5th June 2020, compared with 67% mortality in 90 controls (three weeks prior to availability of tocilizumab) with persistent hypoxia due to severe COVID pneumonia14. At three weeks follow-up 11 / 151(15.7%) patients were still hospitalized. Two of them died later, increasing mortality to 50% in tocilizumab group. In a retrospective observational study in COVID 19 patients treated in ICU in New Jersey, Noa et al15 reported 49% mortality in 210 patients treated with tocilizumab and 61% mortality in 420 patients who did not receive tocilizumab. In present study, 60 out of our 151 patients from tocilizumab group were managed in COVID ICU. Due to non-availability of COVID ICU beds, 15 patients received non-invasive ventilation (NIV) in covid wards, and 7 patients received oxygen through high flow nasal canula (HFNC) in covid wards. Non invasive ventilation was used in 56 patients from tocilizumab group (15 of them later required invasive ventilation) but in none from control group (it was avoided initially due to fear of aerosolization causing increased risk to health care workers).Overall, 30 patients required invasive ventilation (22 from tocilizumab group and 8 from control group. Many investigators, for example Kewan9, Nicola8 have used early Tocilizumab in Covid 19 treatment. Nicola et al7 used tocilizumab in patients with peripheral Oxygen saturation 93% on room air or PaO2/FiO2 less than 300mm of Hg, and documented reduction in mortality from 50% to 7.7%. With early use of tocilizumab, Nicola et al8 could reduce risk of death by 94%. Although more than 70% of our admitted patients were hypoxic (Oxygen saturation less than 95% on ambient air) during hospital stay, the limited availability of tocilizumab made it mandatory for us to formulate strict inclusion criteria for tocilizumab administration. These criteria were formulated by consensus of department members and approved by institutional ethics committee. (saturation 94% or less on 15L per min supplemental Oxygen through non-rebreathing mask or PaO2/FiO2 less than 200). Depending upon inclusion criteria for use of tocilizumab in severe Covid19 pneumonia, severity of disease at the time of intervention and primary outcomes various outcomes are reported. Guaraldi et al7 reported mortality in tocilizumab versus standard care group to be 7% and 20% respectively (P<.0001), with inclusion criteria being respiratory rate more than or equal to 30 per min, Oxygen saturation less than or equal to 93% on room air or PaO2/FiO2 ratio being 300 or less, and bilateral lung infiltrates more than 50% being present within 24 to 48 of admission. Average PaO2/FiO2 ratio in their study was 169 in tocilizumab group as against 277 in standard care group. They also reported the effect of tocilizumab was at least two times higher in people with a baseline PaO2/FiO2 ratio of less than 150 mm Hg, implying that the benefit of tocilizumab could be greater in patients with a greater risk of death or mechanical ventilation.7 Rossotti et al16 reported tocilizumab use to be associated with a better overall survival (HR 0.499 [ 95% CI 0.262-0.952], p=0.035) as compared to control, their inclusion criteria being respiratory rate more than or equal to 30 per min, Oxygen saturation less than or equal to 93% on room air or PaO2/FiO2 ratio being 300 or less. In STOP-COVID trial17 (large multicenter observational comparative study from USA, in ICU admitted Covid-19 patients receiving tolicizumab within 48 hours of ICU admission versus non-tocilizumab cohort, with 419 and 3492 patients respectively after inverse probability weighting to match baseline characteristics and severity of illness, retrospectively analyzed), Gupta et al, reported 28.9% mortality in those treated with tocilizumab and 40.6% in not treated with tocilizumab. During a median follow-up of 27 days, patients treated with tocilizumab were reported to have a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95%CI, 0.56-0.92), and on stratification as per severity of hypoxaemia as PaO2/FiO2 ratio on ICU admission (HRs, 0.88 [95% CI, 0.58-1.35] for ≥200 mm Hg or no mechanical ventilation and 0.59 [95% CI, 0.43-0.81] for <200mmHg and mechanical ventilation. The recently published Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial18 found that dexamethasone reduces mortality in hospitalized patients with COVID-19.The beneficial effect of dexamethasone was particularly pronounced in patients receiving invasive mechanical ventilation. These early data suggest that medications targeting dysregulated inflammation may be a promising therapeutic strategy among critically ill patients with COVID-19. But in published randomized control trials on tocilizumab in Covid19, the effect of tocilizumab on mortality are discordant with the results of observational studies. Possible reasons could be study design, different study population, severity of illness and timing of administration of tocilizumab.
So far 5 RCTs are completed 19,20,21,22, four of them are published and 1 press release23 given by investigators. In BACC (randomized, double-blind, placebo-controlled) trial19, 16% patients did not require supplemental O2, 80% required less than 6L per min O2. Though average saturation and PaO2/FiO2 ratio is not mentioned, over 90% patients had mild disease severity. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64). Authors have not ruled out possibility of some benefit or harm due to wide CI, though tocilizumab was not effective for preventing intubation or death. In the sample size calculations for this trial, the authors assumed an event rate for the primary outcome of 30% in the placebo group and 15% in the tocilizumab group. However, only 27 patients (11.2%) had a primary-outcome event (19 [7.8%] were intubated and 8 [3.3%] died without having been intubated). This represents an event rate that was lower than anticipated for both groups, which is likely to have limited the ability to discern a treatment effect.24 In CORIMUNO-TOCI-19 (open label RCT) by Hermine et al20, patients with PaO2/FiO2 200-300 were included, whereas those from ICU/ on HFNC/NIV/MV (mechanical ventilator) were excluded, on day 14 12% reduction in need for MV or death was reported, but no reduction in death on day 28. In RCT-TCZ-COVID-19 by Salvarani et al21 included patients with PaO2/FiO2 200-300, average being 264, with average CRP 8.2, there was no benefit in achieving primary outcome ( death/ MV/ PaO2:FiO2<150) with tocilizumab. In this study among the 17 patients reaching one primary endpoint (PaO2/FiO2 <150) in the standard care group, 14 received tocilizumab as a rescue therapy (as per protocol). At 30 days, the incidence of intubation and death was comparable between the 2 groups. One can infer that the early administration of tocilizumab does not provide any significant advantage in reduction of intubation or mortality over a deferred administration at PaO2/FiO2 ratio less than 150mmHg. In COVACTA trial22 (randomized, double-blind, placebo-controlled), which reported no mortality benefits on 28 day with tocilizumab, eligibility criteria were broad, viz. patients with saturation less than 94% on room air, which also enrolled 37% patients on MV.
Regarding EMPACTA23, yet to be published, details obtained from clinicaltrials.gov25 and press release from Roche23. It included patients with saturation less than 94% at room air. Whereas EMPACTA trial, with similar inclusion criteria was conducted in minority groups (blacks, Hispanics, Asians), who have higher risk of death, 44% reduction in need for mechanical ventilator or death was reported.
In a meta-anlysis by Tleyhej et al26 which included 5 completed RCTs (1325 patients) and 18 cohort studies (9850 patients), authors report Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. The authors state that the sample size required for an RCT to detect an RR of 0.73 for mortality with tocilizumab (with 80% power and α 0.05) is 4506 patients (2253 in each arm). The total number of patients in the five RCTs is 772 patients in the tocilizumab group and 553 patients in the control group.
Press release from ongoing REMAP-CAP trial27 on 19th November stated tocilizumab was 99 per cent more likely to reduce deaths and time spent in intensive care among critically ill patients with severe COVID-19, compared to patients who did not receive the treatment. REMAP-CAP trial inclusion criteria are patients admitted to ICU with severe pneumonia requiring respiratory support such as high-flow nasal oxygen, continuous positive airway pressure (CPAP) or non-invasive ventilation, or invasive mechanical ventilation and COVID-19 infection confirmed by microbiological testing or where a multidisciplinary team has a high level of confidence that the clinical and radiological features suggest that COVID-19 is the most likely diagnosis). On 25th November, Interim position statement28 given by NHS England is, ‘until the full data from the REMAP-CAP and RECOVERY trials are available, the off-label use of tocilizumab within critical care should follow the criteria and information described in this interim clinical position. The trial Data and Safety Monitoring Board (DSMB) has determined that it is ethically imperative to withdraw the standard-of-care control arm of the immune modulator domain of the REMAP-CAP trial.’
In the current study, clinical response in terms of reduction in Oxygen requirements and respiratory rate was observed within 24-72 hours of tocilizumab infusion in those who responded. C-reactive Protein improved by day 3 to 4. Amongst patients who received tocilizumab, D-dimer levels were higher in ‘non-survived’ group than in ‘survived’ group. Although this difference was not statistically significant, suspicion of terminal pulmonary thromboembolic event was high on clinical grounds in the non-survived group. Zhou et al29 reported D-dimer more than 1000 nanogram/ml to be a risk factor for mortality. A Chinese group30 and BACC supplementary data19 have reported that coagulation abnormalities probably did not improve with tocilizumab. Our clinical impression is that patients in whom clinical improvement in terms of reduced Oxygen requirement did not occur had either extensive lung involvement or high D-dimer or pulmonary thrombi on CT-Pulmonary angiography ( imaging could not be performed in all patients due to logistics issues in patients on High Flow Nasal Canula or on non-invasive or mechanical ventilators). In 26 patients HRCT chest could be performed, all had CO-RAD score31 6 (1 lowest to 6 highest suspicion) and average CT-severity score32 was 21 out of 25. A study from Wuhan33 reported maximum CT score higher than 11 was associated with development of severe illness. CT-pulmonary angiography was performed in 9 patients, and documented pulmonary thrombi in 3 patients. CT-brain was performed in 3 patients and documented brain infracts in all. One patient with pulmonary thrombus developed two large infarcts in brain despite full dose heparin and streptokinase for pulmonary thrombus. Radiological imaging was not possible in more severely affected patients due to them being on advanced respiratory support.
The possibility of secondary infection due to immunosuppressants (steroids and tocilizumab), contributing to morbidity, also has to be considered in both Tocilizumab and control groups, though higher antibiotics like Piperacilin Tazobactum or Meropenem / Vancomycin were used in all critically ill patients. Procalcitonin levels could not be done due to cost constraints. Presence or absence of any co-morbidity did not affect primary out come in the current study.