Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2021 Aug 12;16(8):e0251378.
doi: 10.1371/journal.pone.0251378. eCollection 2021.

The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study

Jovana Milic  1 , Federico Banchelli  2   3 , Marianna Meschiari  4 , Erica Franceschini  4 , Giacomo Ciusa  4 , Licia Gozzi  4 , Sara Volpi  4 , Matteo Faltoni  4 , Giacomo Franceschi  4 , Vittorio Iadisernia  4 , Dina Yaacoub  4 , Giovanni Dolci  4 , Erica Bacca  4 , Carlotta Rogati  4 , Marco Tutone  4 , Giulia Burastero  4 , Alessandro Raimondi  4 , Marianna Menozzi  4 , Gianluca Cuomo  4 , Luca Corradi  4 , Gabriella Orlando  4 , Antonella Santoro  4 , Margherita Digaetano  4 , Cinzia Puzzolante  4 , Federica Carli  4 , Andrea Bedini  4 , Stefano Busani  4 , Massimo Girardis  5 , Andrea Cossarizza  3 , Rossella Miglio  2   3 , Cristina Mussini  1   4 , Giovanni Guaraldi  1   4 , Roberto D'Amico  2   3
Affiliations
Observational Study

The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study

Jovana Milic et al. PLoS One. .

Abstract

Background: The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery.

Methods: In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery.

Results: Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2-5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1-0.7) or in OT (HR = 0.1, 95% CI = 0.0-0.8) treated with tocilizumab.

Conclusion: To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Representation of clinical pathways and number of observed changes of state.
Notes: Arrows represent transitions between states and the number of observed transitions is reported. The dotted lines represent the final transitions of the study. NRS = No Respiratory Support; OT = Oxygen Therapy; NIV = Non-Invasive Ventilation; IMV = Invasive Mechanical Ventilation. 256 patients have started their hospitalization in the NRS state, 12 in the OT state and 3 in the NIV / INT state A total number of 64 patients with censored length of hospital stay were present: 3 in NRS, 9 in OT, 16 in NIV-IMV, 21 in OT in recovery, 15 in NRS in recovery.
Fig 2
Fig 2. The predicted prevalence of patients in each respiratory support state was estimated in the stack probability plot, comparing patients who were treated with tocilizumab from the OT state onwards (left plot) and patients who were not treated with tocilizumab during hospitalization (right plot).
Color code: black = death; blue = discharge; red = non-invasive ventilation/invasive mechanical ventilation; orange = oxygen therapy; green = no respiratory support. The strikethrough area refers to NRS or OT, whereas the “clean” areas refer to NRS or OT in recovery.
See this image and copyright information in PMC

References

    1. Thorlund K, Dron L, Park J, Hsu G, Forrest JI, Mills EJ. A real-time dashboard of clinical trials for COVID-19. Lancet Digit Heal [Internet]. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license; 2020; 2(6):e286–e287. Available from: doi: 10.1016/S2589-7500(20)30086-8 - DOI - PMC - PubMed
    1. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet [Internet]. Elsevier Ltd; 2020; 0(0):1–10. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673620310229 doi: 10.1016/S0140-6736(20)31022-9 - DOI - PMC - PubMed
    1. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med [Internet]. 2020;: 1–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32187464 doi: 10.1056/NEJMoa2001282 - DOI - PMC - PubMed
    1. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med [Internet]. 2020;: 1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32275812 doi: 10.1056/NEJMoa2007016 - DOI - PMC - PubMed
    1. Harris MS, Levy JM, Journal TA, Care M. Clinical Outcomes of Hydroxychloroquine in Hospitalized Patients with COVID-19: A Quasi-Randomized Comparative Study—Confidential—For Rewvie On ly. N Engl J Med. 2020; UNPUBLISHE:2–5.

Publication types

Substances