Published online Jul 9, 2022. doi: 10.5492/wjccm.v11.i4.269
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
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.
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.
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.
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.
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.
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.
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.