Tocilizumab Efficacy Across Inflammatory Subphenotypes in COVID-19-Related Acute Respiratory Distress Syndrome

Daan F L Filippini; Jessica Khyali; Malou Janssen; Emma Rademaker; Olaf L Cremer; Tom van der Poll; Rombout B E van Amstel; Henrik Endeman; Lieuwe D J Bos

doi:10.1097/CCE.0000000000001392

Tocilizumab Efficacy Across Inflammatory Subphenotypes in COVID-19-Related Acute Respiratory Distress Syndrome

Daan F L Filippini^*
, Jessica Khyali
, Malou Janssen
, Emma Rademaker
, Olaf L Cremer
, Tom van der Poll
, Rombout B E van Amstel
, Henrik Endeman
, Lieuwe D J Bos
,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVES: This study evaluated whether the established efficacy of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, differs between the hypoinflammatory and hyperinflammatory subphenotypes.

DESIGN: Retrospective analysis of data from three biobanks.

SETTING: ICUs of three university teaching hospitals in the Netherlands.

PATIENTS: Mechanically ventilated patients with COVID-19.

INTERVENTIONS: Tocilizumab administration vs. no administration.

MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included. Based on a classifier model incorporating IL-6, tumor necrosis factor receptor 1, and bicarbonate, 95% were classified as Hypoinflammatory and 5% as Hyperinflammatory. Tocilizumab was associated with a significant reduction in 30-day mortality in the overall cohort, even after adjustment for confounders (p = 0.014). However, there was no evidence that treatment effectiveness differed between the two subphenotypes (p = 0.59).

CONCLUSIONS: In this cohort, tocilizumab significantly reduced 30-day mortality overall. Although the number of Hyperinflammatory patients was low, there was no evidence that its efficacy differed between inflammatory subphenotypes. These findings underscore the importance of including both subphenotypes in future trials evaluating the differential effects of tocilizumab.

Original language	English
Article number	e1392
Journal	Critical care explorations
Volume	8
Issue number	3
DOIs	https://doi.org/10.1097/CCE.0000000000001392
Publication status	Published - 1 Mar 2026

Keywords

Aged
Antibodies, Monoclonal, Humanized/therapeutic use
COVID-19 Drug Treatment
COVID-19/mortality
Female
Humans
Inflammation
Intensive Care Units
Interleukin-6/blood
Male
Middle Aged
Netherlands/epidemiology
Phenotype
Receptors, Interleukin-6/antagonists & inhibitors
Respiration, Artificial
Respiratory Distress Syndrome/drug therapy
Retrospective Studies
SARS-CoV-2
Treatment Outcome

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@article{4ce88da8ea434cfb9c2eb5cd785132bf,

title = "Tocilizumab Efficacy Across Inflammatory Subphenotypes in COVID-19-Related Acute Respiratory Distress Syndrome",

abstract = "OBJECTIVES: This study evaluated whether the established efficacy of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, differs between the hypoinflammatory and hyperinflammatory subphenotypes.DESIGN: Retrospective analysis of data from three biobanks.SETTING: ICUs of three university teaching hospitals in the Netherlands.PATIENTS: Mechanically ventilated patients with COVID-19.INTERVENTIONS: Tocilizumab administration vs. no administration.MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included. Based on a classifier model incorporating IL-6, tumor necrosis factor receptor 1, and bicarbonate, 95\% were classified as Hypoinflammatory and 5\% as Hyperinflammatory. Tocilizumab was associated with a significant reduction in 30-day mortality in the overall cohort, even after adjustment for confounders (p = 0.014). However, there was no evidence that treatment effectiveness differed between the two subphenotypes (p = 0.59).CONCLUSIONS: In this cohort, tocilizumab significantly reduced 30-day mortality overall. Although the number of Hyperinflammatory patients was low, there was no evidence that its efficacy differed between inflammatory subphenotypes. These findings underscore the importance of including both subphenotypes in future trials evaluating the differential effects of tocilizumab.",

keywords = "Aged, Antibodies, Monoclonal, Humanized/therapeutic use, COVID-19 Drug Treatment, COVID-19/mortality, Female, Humans, Inflammation, Intensive Care Units, Interleukin-6/blood, Male, Middle Aged, Netherlands/epidemiology, Phenotype, Receptors, Interleukin-6/antagonists \& inhibitors, Respiration, Artificial, Respiratory Distress Syndrome/drug therapy, Retrospective Studies, SARS-CoV-2, Treatment Outcome",

author = "Filippini, \{Daan F L\} and Jessica Khyali and Malou Janssen and Emma Rademaker and Cremer, \{Olaf L\} and \{van der Poll\}, Tom and \{van Amstel\}, \{Rombout B E\} and Henrik Endeman and Bos, \{Lieuwe D J\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2026 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.",

year = "2026",

month = mar,

day = "1",

doi = "10.1097/CCE.0000000000001392",

language = "English",

volume = "8",

journal = "Critical care explorations",

issn = "2639-8028",

publisher = "Lippincott Williams \& Wilkins",

number = "3",

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T1 - Tocilizumab Efficacy Across Inflammatory Subphenotypes in COVID-19-Related Acute Respiratory Distress Syndrome

AU - Filippini, Daan F L

AU - Khyali, Jessica

AU - Janssen, Malou

AU - Rademaker, Emma

AU - Cremer, Olaf L

AU - van der Poll, Tom

AU - van Amstel, Rombout B E

AU - Endeman, Henrik

AU - Bos, Lieuwe D J

PY - 2026/3/1

Y1 - 2026/3/1

N2 - OBJECTIVES: This study evaluated whether the established efficacy of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, differs between the hypoinflammatory and hyperinflammatory subphenotypes.DESIGN: Retrospective analysis of data from three biobanks.SETTING: ICUs of three university teaching hospitals in the Netherlands.PATIENTS: Mechanically ventilated patients with COVID-19.INTERVENTIONS: Tocilizumab administration vs. no administration.MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included. Based on a classifier model incorporating IL-6, tumor necrosis factor receptor 1, and bicarbonate, 95% were classified as Hypoinflammatory and 5% as Hyperinflammatory. Tocilizumab was associated with a significant reduction in 30-day mortality in the overall cohort, even after adjustment for confounders (p = 0.014). However, there was no evidence that treatment effectiveness differed between the two subphenotypes (p = 0.59).CONCLUSIONS: In this cohort, tocilizumab significantly reduced 30-day mortality overall. Although the number of Hyperinflammatory patients was low, there was no evidence that its efficacy differed between inflammatory subphenotypes. These findings underscore the importance of including both subphenotypes in future trials evaluating the differential effects of tocilizumab.

AB - OBJECTIVES: This study evaluated whether the established efficacy of tocilizumab, an interleukin-6 (IL-6) receptor antagonist, differs between the hypoinflammatory and hyperinflammatory subphenotypes.DESIGN: Retrospective analysis of data from three biobanks.SETTING: ICUs of three university teaching hospitals in the Netherlands.PATIENTS: Mechanically ventilated patients with COVID-19.INTERVENTIONS: Tocilizumab administration vs. no administration.MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included. Based on a classifier model incorporating IL-6, tumor necrosis factor receptor 1, and bicarbonate, 95% were classified as Hypoinflammatory and 5% as Hyperinflammatory. Tocilizumab was associated with a significant reduction in 30-day mortality in the overall cohort, even after adjustment for confounders (p = 0.014). However, there was no evidence that treatment effectiveness differed between the two subphenotypes (p = 0.59).CONCLUSIONS: In this cohort, tocilizumab significantly reduced 30-day mortality overall. Although the number of Hyperinflammatory patients was low, there was no evidence that its efficacy differed between inflammatory subphenotypes. These findings underscore the importance of including both subphenotypes in future trials evaluating the differential effects of tocilizumab.

KW - Aged

KW - Antibodies, Monoclonal, Humanized/therapeutic use

KW - COVID-19 Drug Treatment

KW - COVID-19/mortality

KW - Female

KW - Humans

KW - Inflammation

KW - Intensive Care Units

KW - Interleukin-6/blood

KW - Male

KW - Middle Aged

KW - Netherlands/epidemiology

KW - Phenotype

KW - Receptors, Interleukin-6/antagonists & inhibitors

KW - Respiration, Artificial

KW - Respiratory Distress Syndrome/drug therapy

KW - Retrospective Studies

KW - SARS-CoV-2

KW - Treatment Outcome

U2 - 10.1097/CCE.0000000000001392

DO - 10.1097/CCE.0000000000001392

M3 - Article

C2 - 41837874

SN - 2639-8028

VL - 8

JO - Critical care explorations

JF - Critical care explorations

IS - 3

M1 - e1392

ER -

Tocilizumab Efficacy Across Inflammatory Subphenotypes in COVID-19-Related Acute Respiratory Distress Syndrome

Abstract

Keywords

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