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Neither earlier nor late tocilizumab improved outcomes in the intensive care unit patients with COVID-19 in a retrospective cohort study
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  1. Sergey Moiseev1,
  2. Sergey Avdeev2,
  3. Ekaterina Tao1,
  4. Michail Brovko1,
  5. Nikolay Bulanov1,
  6. Anastasiia Zykova3,
  7. Larisa Akulkina1,
  8. Irina Smirnova1,
  9. Victor Fomin4
  1. 1Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
  2. 2Clinic of Pulmonology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
  3. 3Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russian Federation
  4. 4Vinogradov Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
  1. Correspondence to Professor Sergey Moiseev, Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow 119435, Russian Federation; avt420034{at}yahoo.com

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Tocilizumab (TCZ), a recombinant monoclonal antibody against the interleukin (IL)-6 receptor, has been proposed as a potential therapy for severe SARS-CoV-2 pneumonia based on observational studies.1 Recently, a strategy involving a course of high-dose glucocorticoids, followed by TCZ if needed (in 43% of patients), was shown to improve mortality in patients with rapid respiratory deterioration plus elevation of at least two out of three biomarkers (C reactive protein (CRP), ferritin and/or D-dimer).2 Nevertheless, a short-term use of TCZ is not free from serious adverse events, and the efficacy data, although promising, are preliminary.3

The timing of anti-inflammatory treatments in relation to the stage of disease seems to be important in patients with COVID-19.4 Therefore, the objective of our retrospective study was to assess the efficacy of earlier and late intravenous TCZ, that is, prior to and after initiation of mechanical ventilation, respectively, in reducing mortality in a cohort of patients with severe COVID-19 pneumonia who required support in intensive care unit (ICU).

In March 2020, the Russian Ministry of Health set up a Federal Center at the Sechenov University (Moscow) to provide virtual support for the ICU physicians caring for patients with COVID-19.5 All local COVID-19 hospitals were proposed to submit medical records of critically ill patients via secure network to the Federal Center giving urgent advice on the critical care management. For this study, we selected consecutive ICU patients whom TCZ administration was recommended given the presence of bilateral pneumonia involving at least 50% of lung tissue and requiring respiratory support, particularly if associated with an increased CRP) level. The final decision to use TCZ was at the discretion of the treating clinician. Our consultants were not aware of the IL-6 inhibitors availability in medical institutions and could not predict whether TCZ would be administered or not. The dose of intravenous TCZ was 400 mg as suggested by the provisional recommendations of the Russian Ministry of Health. Only patients with known outcomes, that is, death or recovery, were enrolled in this study. The primary outcome of in-hospital all-cause mortality was compared between patients who received TCZ and those who did not using logistic regression model, since Cox regression model validity was not confirmed by evaluation of the proportional hazards assumption using Schoenfeld residuals.

Between 16 March and 5 May 2020, we received medical records of 2066 patients with a diagnosis of COVID-19 who were admitted to the ICUs for worsening oxygenation. In this sample, 328 patients (57.0% males, median age of 59 years) were considered eligible for TCZ administration. One hundred and fifty-nine of 328 patients received at least one 400 mg flat dosing of TCZ (21 patients received two infusions with an interval of around 24 hours), whereas the remaining 169 patients were not treated with IL-6 inhibitor usually due to the shortage of medication. TCZ was administered to 83 (60.1%) of 137 patients who needed oxygen therapy or non-invasive ventilation at the point of infusion or submission of medical record by the local hospital (earlier TCZ cohort) and to 76 (39.8%) of 191 intubated patients (late TCZ cohort) (figure 1). TCZ was administered a median of 6 days (IQR 3–9) from the date of hospitalisation in the former cohort, and a median of 2 days (IQR 1–4) from intubation in the latter cohort.

Figure 1

Flow of patients. Note: the percentage of patients who were considered eligible for TCZ was relatively low since at the beginning of the outbreak of COVID-19 in Russia IL-6 inhibitors were not widely used due to a lack of data. ICU, intensive care unit; IL, interleukin; TCZ, tocilizumab.

In the total population, the mortality rates did not differ between patients who received TCZ infusion and those who were not treated with IL-6 inhibitor (46.5% and 50.3%, respectively, p=0.509). In both groups, the most common causes of death were acute respiratory distress syndrome (91.9% and 77.6%, respectively), cardiovascular complications (5.4% and 12.9%) and pulmonary embolism (1.4% and 2.4%). In the earlier TCZ cohort, the mortality rate was twofold lower than in the late TCZ cohort (32.5% and 61.8%, p<0.001). However, neither earlier nor late TCZ administration resulted in a lower risk of death compared with patients who did not receive TCZ infusion. Age and gender adjusted ORs of death in patients treated with earlier and late TCZ were 2.370 (95% CI 0.969 to 5798; р=0.059) and 0.996 (95% CI 0.539 to 1.839; р=0.989), respectively, compared with untreated patients. Moreover, the earlier TCZ infusion was associated with a higher requirement for mechanical ventilation that retained statistical significance after adjustment for age and gender (OR 2.507; 95% CI 1.184 to 5.310; р=0.016). This finding could be partly explained by a higher prevalence, although insignificant, of several comorbidities impairing prognosis, that is, coronary artery disease, stroke and type 2 diabetes, in the TCZ group (table 1). Intubated patients who received TCZ and those who did not were well matched by demographic parameters and the prevalence of significant comorbidities. Therefore, it seems unlikely that the differences between groups could contribute to the negative results of our study in this population.

Table 1

Demography, clinical characteristic and outcomes of patients with severe COVID-19 pneumonia

Our findings are in contrast with the results of multiple previous observational studies6–9 and preliminary unpublished results of the phase II French CORIMUNO-TOCI trial, which suggested a reduction in mortality and requirement for mechanical ventilation in patients who received TCZ.10 However, the randomised, double-blind, placebo-controlled phase III study (COVACTA, NCT04320615) that evaluated the safety and efficacy of intravenous TCZ in 450 patients hospitalised with severe COVID-19 associated pneumonia failed to meet its primary endpoint of improved clinical status or the key secondary endpoint of reduced patient mortality.11 Another IL-6 receptor antagonist, sarilumab, that showed early promise in retrospective studies also failed in a phase III trial in critically ill COVID-19 patients on mechanical ventilation.12 These trials raise doubts about benefit of IL-6 blockade in COVID-19.

In summary, neither earlier TCZ administration in non-intubated ICU patients with severe COVID-19 associated pneumonia nor late infusion after initiation of mechanical ventilation did reduce mortality. Unfortunately, our findings are in line with the preliminary results of phase III trials of IL-6 inhibitors in patients with severe COVID-19 pneumonia. We agree with Ramiro et al2 that initial immunosuppressive treatment, if considered necessary in these patients, should involve widely available and inexpensive glucocorticoids, whereas IL-6 inhibitors, as chloroquine/hydroxychloroquine,13 may be preserved for patients with rheumatic diseases in whom these medications have established efficacy.

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Footnotes

  • Contributors All authors participate in conducting a study and preparing a manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Ethics Committee of the Sechenov University.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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