IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Abstract

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19.

Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ.

Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality.

Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients.

Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration.

Keywords: COVID-19; IL-6; invasive mechanical ventilation; tocilizumab.

Fig 1

IL-6 serum levels predict disease severity and TCZ use. A, Correlation between log-transformed IL-6 serum levels and PaO₂. B, Correlation between log-transformed IL-6 serum levels and PaO₂/FiO₂. Data in panels A and B are shown as dot-plot and their fitted linear prediction with 95% CI (transparent gray shadow) estimated using the 2-way command of Stata with the lfitci option. C, ROC curve showing the ability of log-transformed IL-6 serum levels to discriminate between patients requiring and not requiring IMV. D, ROC curve for the ability of log-transformed IL-6 serum levels to discriminate between TCZ-treated and nontreated patients. The best cutoff for discrimination of patients requiring IMV (Fig 1, C) or TCZ treatment (D) was 30 pg/mL.

Fig 2

Response of laboratory parameters to TCZ treatment. Differences in (A) log-transformed IL-6 serum levels, (B) C-reactive protein, and (C) procalcitonin, (D) ferritin, (E) LDH, and (F) D-dimer. Data are presented as the IQR (p75 upper edge, p25 lower edge, p50 midline), p95 (line above the box), and p5 (line below the box) of levels for each parameter before (gray boxes) and after (white boxes) treatment with TCZ. PRE and POST mean first and second evaluation, respectively.

Fig 3

Change in PaO₂/FiO₂ in patients with COVID-19 treated early (before 11 days of symptoms onset) or late with TCZ and not treated. A, Patients with high baseline IL-6 (cutoff 30 pg/mL). B, Subjects with low baseline IL-6 serum levels. Data in A and B are shown as the IQR (p75 upper edge, p25 lower edge, p50 midline), p95 (line above the box), and p5 (line below the box) before (gray boxes) and after (white boxes) treatment with TCZ. In nontreated patients, PRE and POST mean first and second evaluation, respectively. Statistical significance was determined with the Mann-Whitney test. C, The graph represents the predicted mean (dots) with 95% CI (bars) of PaO₂/FiO₂ according to baseline IL-6 levels and early or late TCZ treatment. Data were obtained with the command marginsplot of Stata, after adjustment by baseline PaO₂/FiO₂ and radiological pattern, hypertension, LDH and CRP levels, lymphocyte blood count, and need for IMV, according to the multivariable analysis displayed in Table E2 (see the Methods section for further information).

Fig 4

Survival curves of patients with COVID-19 grouped according to baseline IL-6 levels and TCZ treatment. Statistical significance was established with log-rank test.

Fig E1

Flowchart of patients included in the study.

Fig E2

Histogram showing the daily evolution of COVID-19 cases in Spain according to their clinical situation.

Fig E3

A, Plots showing the distribution of raw IL-6 serum levels in patients (red) vs healthy donors (green). B, Distribution of log-transformed serum IL-6 levels in the former groups. C, ROC curve showing the ability of IL-6 serum levels to classify patients with COVID-19 vs healthy donors. LR+, Positive likelihood ratio; LR−, negative likelihood ratio; Sen, sensitivity; Spe, specificity.