Systematic Reviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Crit Care Med. Jul 9, 2022; 11(4): 269-297
Published online Jul 9, 2022. doi: 10.5492/wjccm.v11.i4.269
Immunomodulatory therapy for the management of critically ill patients with COVID-19: A narrative review
David Andaluz-Ojeda, Pablo Vidal-Cortes, Álvaro Aparisi Sanz, Borja Suberviola, Lorena Del Río Carbajo, Leonor Nogales Martín, Estefanía Prol Silva, Jorge Nieto del Olmo, José Barberán, Ivan Cusacovich
David Andaluz-Ojeda, Department of Critical Care, Hospital Universitario HM Sanchinarro, Hospitales Madrid, Madrid 28050, Spain
Pablo Vidal-Cortes, Lorena Del Río Carbajo, Estefanía Prol Silva, Jorge Nieto del Olmo, Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
Álvaro Aparisi Sanz, Department of Cardiology, Hospital del Mar, Barcelona 08003, Spain
Borja Suberviola, Department of Intensive Care, Hospital Universitario Marqués de Valdecilla, Santander 39008, Spain
Leonor Nogales Martín, Department of Intensive Care, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
José Barberán, Department of Internal Medicine, Hospital Universitario HM Montepríncipe, Hospitales Madrid, Boadilla del Monte 28860, Madrid, Spain
Ivan Cusacovich, Department of Internal Medicine, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
Author contributions: Andaluz-Ojeda D, Vidal-Cortes P, and Cusacovich I designed the study, developed the material and methods section, the introduction and a global discussion; Aparisi Sanz Á, Suberviola B, Del Río Carbajo L, Nogales Martín L, Prol Silva E, Nieto del Olmo J, and Barberán J carried out a selective bibliographic search in relation to each of the study points and developed a partial discussion; and all authors participated in the final recommendations for each class.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and confirm that the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: David Andaluz-Ojeda, MD, PhD, Assistant Professor, Consultant Physician-Scientist, Department of Critical Care, Hospital Universitario HM Sanchinarro, Hospitales Madrid, Oña, 10, Madrid 28050, Spain. davidandaluz78@yahoo.es
Received: July 22, 2021
Peer-review started: July 22, 2021
First decision: November 11, 2021
Revised: December 1, 2021
Accepted: May 16, 2022
Article in press: May 16, 2022
Published online: July 9, 2022
Processing time: 349 Days and 21.5 Hours
ARTICLE HIGHLIGHTS
Research background

Although most people with coronavirus disease 2019 (COVID-19) have only mild or uncomplicated symptoms, 10%-15% requires hospitalization and oxygen therapy and, from the beginning, a large number of patients presented severe respiratory failure, needing mechanical ventilation (MV) and intensive care unit (ICU) admission. The lack of an available, effective treatment in this setting has led to a spate of treatment recommendations, which are not always backed by sufficient scientific evidence. Particular attention were paid to a presumed specific cytokine storm secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with a special effort to modulate the inflammatory response of these patients.

Research motivation

Two years after the onset of the pandemic, many questions remain unanswered, and we continue to search for the most appropriate treatment. This review aims to summarize the current evidence regarding the different immunomodulatory strategies tested in critically ill patients with COVID-19. Most of the main trials that have shown benefit of any immunomodulatory therapeutic agent against COVID-19 focus on hospitalized patients but not on critically ill patients. Furthermore, many of these studies consider ICU admission as a primary negative endpoint. Very few studies consider treatment in this setting (ICU) as a starting point, sometimes unavoidable, given that many patients with COVID-19 required admission to the ICU already in the first hours of their hospital admission. Therefore, there is a lack of information on the therapeutic approach in these patients.

Research objectives

To summarize the pathophysiology of SARS-CoV-2, including the normal and pathological inflammatory and immune responses that would justify the use of different immunomodulatory therapies in critically ill patients. To analyze the mechanism of action of the different immunomodulatory agents used against COVID-19. Review the scientific evidence collected so far and issue a recommendation for or against the use of each specific agent in this scenario.

Research methods

A comprehensive literature search was developed by using the keywords: “immunotherapy”, “immunosuppressives”, “haemophagocytic syndrome”, “inflammation”, “antimalarials”, “hydroxychloroquine”, “chloroquine”, “anakinra”, “canakinumab”, “tocilizumab”, “sarilumab”, “corticosteroids”, “dexamethasone”, “methylprednisolone”, “immunoglobulins or convalescent” “JAK inhibitors”, “cyclosporine”, “colchicine”, “statins”, “interleukin 7”, “tymosin”, “PD1 and PD-L1 blockers”. We restricted the search to: “SARS-CoV-2”, “COVID-19”, “severe COVID-19” and “treatment” to identify articles published in English from MEDLINE, PubMed, and The Cochrane Library (until January 2021). The authors reviewed the selected manuscripts and selected the most appropriate. Finally, we established a recommendation of the use of each treatment based on the level of evidence of the articles and documents reviewed. This recommendation was made based on the consensus of all the authors. We carried out the rest of the work methodology following the PRISMA recommendations.

Research results

Different recommendations regarding the use of these immunomodulatory agents (“antimalarials”, “hydroxychloroquine” “chloroquine”, “anakinra”, “canakinumab”, “tocilizumab”, “sarilumab”, “corticosteroids”, “dexamethasone”, “methylprednisolone”, “immunoglobulins or convalescent”, “JAK inhibitors”, “cyclosporine”, “colchicine”, “statins”, “interleukin 7”, “tymosin”, “PD1 and PD-L1 blockers”) were performed.

Research conclusions

Until then, although several promising therapies exist, only the use of corticosteroids and tocilizumab (or sarilumab in absence of this) has demonstrated evidence enough to recommend its use in critically ill patients with COVID-19. Probably other treatments of those analyzed could be beneficial in certain critical patients with COVID-19 if they were administered in a selective and personalized way.

Research perspectives

From this work, two simple and clear messages can be extracted that could guide the future therapeutic approach of severe forms of COVID-19: (1) The critically ill patient constitutes a special subgroup of patients that should be studied differently from other patients, considering the ICU as an initial and not a final stage in the course of the disease; and (2) It is a mistake to administer the same treatments to all patients. It is key to individualize these treatments based on the immunological and clinical phenotypes of each patient.