Patients with COVID-19 are known to develop a major inflammatory response that can lead to acute respiratory distress syndrome (ARDS). As inflammation is thought to contribute to the pathogenesis of ARDS1 it warrants further investigation as to the pharmacokinetic effects of immunomodulatory agents. Further study of the interaction of these drugs with virus/host dynamics is necessary to provide insight into optimal timing of administration, dosing, and association with other interventions.

Corticosteroids are potent anti-inflammatory agents with immunomodulatory properties, which exert inhibitory effects in several stages of the inflammatory cascade, and consequently have been proposed for the treatment of ARDS.2–3 However, in recent epidemics due to coronavirus infections such as that Middle East respiratory syndrome-related coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome associated coronavirus (SARS-CoV) or influenza viruses the use of corticosteroids was associated with delayed virus clearance and an increase in ICU mortality.4–7

Several randomized control trials8–10 found a benefit to the use of corticosteroids in patients with COVID-19, and various clinical guidelines11,12 recommended its use to all patients requiring oxygen with severe COVID-19 during the second wave. However, there is limited data in relation to ICU admission beyond 28 days that assesses the side effects of medium- and long-term glucocorticoid treatment.13–14 For example, there are still unanswered questions as which subgroup or rather “phenotype” of patients could have higher response rate to the steroid therapy.15 Therefore, our primary objective is to identify the association of corticosteroids treatment in a whole cohort population and according to three new classified clinical phenotypes identified from 2017 COVID-19 critically ill patients in Spain.16 Our secondary objective is to stratify the competing risk factors associated with use of corticosteroids in each phenotype and clinical outcome.

This represents the first built machine learning model used to assess the effect of corticosteroids therapy according to pre-defined clinical phenotypes among a large cohort of critically ill patients with severe COVID-19 disease. The main finding of our study is that the use of corticosteroids was not associated with improved outcomes in all critically ill patients with COVID-19 at moderate dose.

The challenge in developing optimal treatment strategies is the extreme heterogeneity of presentation in COVID-19 patients who are critically ill.15–16 Consequently, our study suggests that only clinical phenotypes with a high degree of systemic inflammation, such as the defined phenotype C, may have an early benefit from steroid treatment. Benefits offered by corticosteroids in attenuating immune dysregulation must be balanced with their inhibitory effect on the immune response needed to control viral replication, as well as risk of opportunistic infections and associated side-effects.13,14 Specifically, our results show a higher incidence of VAP in patients who have received corticosteroids in B and C phenotypes.

Data from the RECOVERY Trial8 and WHO meta-analysis,11 supported the administration of 6mg dexamethasone for all patients with COVID-19 who required oxygen supplementation or IMV. However, the role of corticosteroids in the treatment of COVID-19 remains controversial.23–29 A recent study in France30 comparing first vs. second wave reported that, despite of the systematic and early administration of glucocorticoids in the second wave, the ICU mortality (50% vs. 52%, p=0.96) and duration of ICU stay did not differ between the two waves. In contrast, Wu et al.31 observed in 380 patients that, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed ARDS. However, it should be noted that this study only included patients with ARDS, and corticosteroids were initiated 13 days after symptom and this is not the usual clinical practice.

Chen et al.15 observed presence of two phenotypes (hypo and hyper-inflammatory) among COVID-19 patients. Interestingly, after applying a marginal structural modeling, the association between corticosteroid therapy and 28-day mortality was only observed in patients with the hyper-inflammatory phenotype. These findings are consistent with our results, where only the phenotype C (with a higher inflammatory status), seem to have benefit from corticosteroid treatment. This observation is contrary to the current recommendation of dexamethasone treatment according to the RECOVERY trial,8 that showed that the mortality from COVID-19 was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care. Several limitations have been reported since its publication.2,3,32,33 Possibly the most important limitations are the lack of an adjustment according to severity of illness to minimize potential bias and that mortality has been censored at 28 days, and no data have been published from the mortality at ICU or hospital discharge.

Survival benefit of corticosteroids8 appeared greatest among patients who required IMV. These findings are consistent with our results, as between 70 and 80% of patients in phenotypes B and C required ventilation and then could benefit from steroids. In the other hand, in the RECOVERY trial8 a favorable effect on survival was evident with the use of steroids treatment among patients who only required supplemental oxygen. This sub-group of patients can be said to represent a similar profile to that of the A phenotype from our study, where more than 80% of patients received only supplemental oxygen at ICU admission. However, we do not observe the impact of corticosteroid treatment on survival in this phenotype and our results strongly suggest that corticosteroid treatment should not be administered to patients who do not require mechanical ventilation independently of their hypoxemia level. Differences in results could be due to our patient adjustment modeling according to severity in illness and the absence of stratification and incomplete information about some factors associated with outcome in the RECOVERY trial may have resulted in imbalance between the treated and control.26 In addition, a recent prospective study34 with more than 3000 elderly critically ill COVID-19 patients, observed an independent association of steroid use with increased 30-days mortality after multivariable adjustment (aOR 1.60; 95% CI 1.26–2.04).

However, some study limitations should be noted. First, although phenotypes were found to be generalizable in our population (after validation), risk factors and characteristics that pre-defined these clinical phenotypes were derived initially from data at ICU admission of a multicenter observational study in Spain. However, at the same time these risk factors are similar to those that have been reported by other investigators31,35,36 which suggests its applicability to other populations.

Second, only routinely available clinical data at ICU admission was used to identify risk factors and clinical phenotypes, and the inclusion of other data related to clinical evolution of patients in the ICU could change risk factors or phenotype assignments. However, our objective was to study early risk factors and phenotypes at ICU admission that may allow for early treatment implementation and as a result improve patient outcome.

Third, this is a sub-analysis conducted following the author's primary observational study in order to consider only segmental measured confounders. The authors are aware of the limitations presented by the exclusion of other residual measured confounders and unmeasured confounders that could not be included fully.

Fourth, we cannot affirm that an echocardiographic assessment has been carried out in all patients, so the incidence of cardiac dysfunction may be higher than that observed. This incidence should be considered with caution.

Finally, this study did not collect data that could assess the impact of ethnicity, socioeconomic factors o long-term complications. These factors may play a role in the prevalence of pre-existing comorbidities and mortality due to COVID-19.

Our findings warn against the widespread use of corticosteroids in all critically ill patients with COVID-19 according to the moderate dose and suggest the need to determine within each phenotype what subset of patients may really benefit from treatment.

Alejandro Rodríguez, Gerard Moreno, Manuel Ruiz-Botella, Ignacio Martín-Loeches, María Jiménez Herrera, Jordi Sole-Violán, Josep Gómez, María Bodí, Sandra Trefler, Fernándo Armestar, Asunción Marques Parra, Angel Estella, Ruth Jorge García, Pablo Vidal-Cortes, Emili Díaz, Ricard Ferrer, Antonio Albaya-Moreno, Ana Loza, Laura Sánchez Montori, María deAlba-Aparicio, Mercedes Nieto, Judith Marín-Corral, Lorena Forcelledo Espina and Immaculada Vallverdú had substantial contributions to conception and design of the work.

Alejandro Rodríguez, Sandra Trefler, Manuel Ruiz-Botella, Ana Casamitjana Ortega, Fátima Martín Serano, Josep Gómez, Josep María Bonell Goytisolo, Susana Sancho Chinesta, Virgina Fraile Gutierrez, Angel Estella and Lorenzo Socias Crespi had substantial contribution for data acquisition.

Alejandro Rodríguez, Gerard Moreno, Manuel Ruiz-Botella, Ignacion Martín-Loeches, Josep Gomez, María Bodí, Judith Marín-Corral, Antonio Alabaya Moreno and Angel Estella had substantial contribution for data analysis and interpretation of data for the work.

Alejandro Rodríguez, Gerard Moreno, Ignacio Martín-Loeches, Josep Gómez and Emili Díaz drafting of the manuscript.

Ricard Ferrer, María Bodí, Judith Marín-Corral, Juan Carlos Pozo Laderas, Antonio Albaya Moreno and Jordi Solé-Violán critically reviewed the draft manuscript.

The corresponding author (Alejandro Rodríguez) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of the manuscript. The views expressed in this article are those of the authors and not necessarily those of the SEMICYUC.

This study was supported by the Spanish Intensive Care Society (SEMICYUC), Ricardo Barri Casanovas Foundation Grant (A. Rodríguez) and Grant of Pla Estratègic de Recerca i Innovació en Salut-Generalitat de Catalunya PERIS SLT017/20/000030 (M. Bodi, M. Ruíz-Botella, J. Gómez, A. Rodríguez). The study sponsors have no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

All authors declare that they have no conflicts of interest.