Temporal clinical and laboratory response to interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia

Abstract

Background:. Emerging evidence links morbidity and mortality of pandemic COVID-19 pneumonia to an inflammatory cytokine storm. Methods: Eighty nine patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) were treated with Tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor. Results: Clinical and laboratory improvement was seen comparing baseline and 1-2 day post-infusion indices. Among 72 patients not receiving mechanical ventilation, NEWS2 scores fell from 5 to 2 (p <0.001) C reactive protein levels fell from 95 to 14 mg/L (p <0.001) and lymphocyte counts rose from 900 to 1000/uL (p=0.036). Sixty three of 72 patients were discharged from hospital, one patient died, and 8 remained in hospital at time of writing. Among 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (p = 0.014) and early improvements in NEWS2 scores in 10 of 17, ten patients died and seven remain in hospital at time of writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration. Conclusions: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of Tocilizumab, an anti IL-6 receptor antibody is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review

“…All patients discharged on average 15.1 day after tocilizumab. By day 5 after TCZ, 75.0% of patients had lower oxygen intake Poor quality score (NOS) In case of fever within 12 h, single additional dose Pre-print not peer reviewed studies Fomina et al 37 Single-centre retrospective observational study (Russia) Hospitalized patients with COVID-19 (n = 89) Tocilizumab 400 mg No comparison Clinical course 63/72 not mechanically ventilated patients were discharged, 1/72 died, 8/72 remained in hospital; 10/17 mechanically ventilated patients died and 7/10 remain in hospital Poor quality score (NOS) Gorgolas et al 36 Single-centre retrospective observational study (Spain) Hospitalized patients with COVID-19 (n = 186) Tocilizumab single dose of 400−600 mg (16 received two doses and 1 received three doses) No comparison Intubation or death after 24 h from administration 51 patients were intubated or dead at day 15; 19 patients needed intubation (of whom 4 died) and 36 died (32 of whom were not intubated). 11 (5·9%) patients had serious adverse reactions, 13 cases (6·3%) of secondary acquired infections Poor quality score (NOS) Ip et al 31 Multicentre, retrospective, observational, study (USA) ICU patients with COVID-19 (n = 547) Tocilizumab: 400 mg (96%), followed by 800 mg (1%), 8 mg/kg (1%), 4 mg/kg (1%), and missing dosing (1%).…”

“…We retrieved 13 published clinical studies 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 and 15 pre-print (i.e. pre peer review) clinical studies, 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 respectively evaluating 1396 and 4380 patients, for a total of 5776 patients. The main characteristics of the included clinical studies are presented in Table 1 .…”

The role of Interleukin 6 inhibitors in therapy of severe COVID-19

“…In a Russian clinical study [ 75 ], 89 patients with COVID-19 received TCZ. Mechanical ventilation was provided for 17 (19%) of these patients; the remaining patients received supplemental oxygen.…”

A review of medications used to control and improve the signs and symptoms of COVID-19 patients

“…There are currently 14 clinical trials on this drug all over the world the result of which is yet to be published ( Jones et al, 2010 ). Another study with 89 patients showed lower mortality and rapid improvement in CRP and lymphocyte counts in addition to clinical indices ( Formina et al, 2020 ).…”