This study is one of the first to investigate the impact of steroids on immunocompromised patients with severe COVID-19 who were admitted to the ICU. Our cohort included 62% of patients with cellular immunodeficiency, 28% with humoral immunodeficiency, 7% who were receiving steroids, and 3% with altered monocyte levels. At the time of ICU admission, most patients were on steroids, primarily dexamethasone. Steroid use did not reduce mortality, nor was associated with an increased risk of nosocomial infections.

These findings warrant several important considerations.

First, it is one the first study to include only immunocompromised critically ill patients. Other studies included hospitalized COVID-19 immunocompromised patients and mainly focused on the consequence of immunodepression itself^36,37. For instance, Turtle et al.¹⁵, based on the WHO ISARIC CCP-UK prospective cohort, reported higher mortality among immunocompromised individuals (29% vs. 21%) and identified an increased mortality risk (aOR 1.44, p < 0.01), but a decreased likelihood of ICU admission and intubation.

Then, our study provides a snapshot of how immunocompromised patients were treated in France between January 2020 and August 2022. In our cohort, 87% of patients received steroids, while 18% received anti-Il6 therapies. No patients received anti-JAK 2 inhibitors, nor did any benefit from adsorption therapy. The high use of steroids likely reflects adherence to guidelines, whereas the lower use of anti-Il6 therapies may suggest caution due to the potential risks of further immune suppression. Only 10% of patients received convalescent plasma, primarily those with humoral deficiencies, despite studies showing benefits of convalescent plasma for immunosuppressed patients³⁸, particularly those with B-cell malignancies³⁹. Similarly, only 6% received remdesivir, despite evidence demonstrating its benefit^40,41. This may be explained by contraindications in patients with renal failure, as well as delayed recommendations for its use^42,43. Finally, less than 1% of our patients received a combination of antivirals, steroids, and passive immunotherapy with hyperimmune convalescent plasma. This combination of treatments has shown promising results and has now been adopted for most immunocompromised patients⁴⁴.

In our study, steroid treatment for severe COVID-19 in immunocompromised patients did not improve vital outcomes. Until nowadays, few studies have evaluated the impact of immunomodulators in immunocompromised patients, mainly focusing on anti-Il1 and anti-Il6 therapies^45,46,47, but not steroids. For example, a cohort of non-ICU hospitalized solid organ transplant patients receiving tocilizumab (24.8%) showed no increased mortality (41% vs. 28%, p = 0.27) or secondary infections (34% vs. 24%, p = 0.55)⁴⁷. More recently, a meta-analysis was achieved¹⁰. Ultimately, 11 trials with 397 immunocompromised patients were included, showing no significant difference in mortality, secondary infections, or change in outcomes between those treated with immunomodulators and controls. Notably, all patients in these trials received steroids regardless of immunomodulator use. The lack of benefit from immunomodulatory treatment may be due, in part, to delayed adaptive responses, prolonged viral replication^43,44, and the occurrence of nosocomial infections, including reactivation of latent infections. Additionally, factors such as worsening adrenal insufficiency, exacerbation of pre-existing sarcopenia with muscle loss, and the development of ICU-acquired weakness may have contributed. Co-infections and secondary infections are a significant issue for patients with severe COVID-19^5,7,8. Immunocompromised patients are particularly susceptible to such complications^48,49. Such a risk was well illustrated, in India, by the increase mucormycosis rates among kidney transplant recipients with COVID-19 surged, with incidences ranging from 4.4% to 10%^44,49,50.

Due to the inconsistent results and limited quality of studies on steroid use, there is no strong recommendation for the use of immunomodulatory therapies in immunocompromised patients with severe COVID-19 admitted to the ICU. However, the Centers for Disease Control and Prevention (CDC) guidelines for immunocompromised COVID-19 patients recommend using immunomodulatory therapies at the same doses and durations as for the general population⁴³.

Immunocompromised patients remain at high risk for severe COVID-19, despite widespread vaccination, natural immunity, and the emergence of new viral variants. The primary reasons include a reduced ability to mount an effective immune response⁵¹, decreased vaccine efficacy^44,52,53, and prolonged viral shedding.

In this context, the use of steroids in immunocompromised COVID-19 patients—as well as in future viral pandemics, particularly those caused by respiratory viruses—requires caution⁵⁴. Contemporary COVID-19 and other viral infections may trigger varying immune responses, and not all involve a similar hyperinflammatory phase. As seen with influenza, steroids may be associated with prolonged viral shedding and an increased risk of secondary infections.

The use of steroids in immunocompromised patients with septic acute respiratory failure remains a complex issue. It is well established that low-dose corticosteroids reduce mortality in critically ill, non-immunocompromised patients with severe community-acquired bacterial pneumonia (CAP)⁵⁵. Steroids have also demonstrated benefits in critically ill patients with respiratory infections, septic shock, or acute respiratory distress syndrome (ARDS)⁵⁶. However, in most randomized controlled trials assessing steroid use, immunocompromised patients represent only a small proportion or are entirely excluded. Notably, a study by Meduri et al.⁵⁷ included 20% immunocompromised patients but did not find a protective effect, unlike other studies that reported benefits from steroids but included fewer than 6% immunocompromised patients^55,58,59.

This study has both strengths and limitations.

Among its strengths, it is a multicenter study with a large cohort of immunocompromised ICU patients. Although the analysis was retrospective, it relied on prospectively collected data. We accounted for multiple confounding factors, including the period of admission, applied propensity score methods to minimize bias, and conducted sensitivity analyses to ensure robustness.

However, the study also has several limitations. The primary concern is the small sample size of the non-steroid group (only 50 patients), which may lead to a type I error. Additionally, there were baseline differences between the steroid and non-steroid groups, including the inclusion period and the severity of hypoxemia at ICU admission. To mitigate these biases, we used inverse probability of treatment weighting (IPTW) with overlap, which is particularly robust when handling imbalanced sample sizes and reduces information loss. Second, our analysis accounted for admission period, IMV, PaO₂/FiO₂ ratio, and anti-interleukin treatments, including anti-IL-6 and anti-IL-1 therapies. However, some potential confounders—such as viral variants, vaccination status, and other treatments including anti-SARS-CoV-2 antibodies, plasmapheresis, C5 inhibitors, Janus kinase inhibitors, and antiviral therapies—were not directly included. Nonetheless, these factors are closely associated with the admission period. Third, some key outcomes were not collected, such as longitudinal viral load measurements. Fourth, the classification of immuno-compromised status may be debated¹⁸; however, we also provided results based on more conventional classifications, including solid organ transplantation and hematologic malignancies. Other subgroup analyses were not feasible due to sample size limitations.

Fifth, immortality bias may have occurred. Patients in the early corticosteroid (CS) group may have had a survival advantage, as they had to survive at least 2 days to receive treatment (defined as at least two doses of steroids within the first 5 days). However, only a small proportion of patients in the early-CS group did not receive steroids on days 1 and 2 (N = 8/333; 2.5%). To address this, we conducted a sensitivity analysis including only patients who survived beyond day 5, which yielded consistent results. Finally, we did not perform a survival analysis differentiating between the types of nosocomial infections, specifically bacterial versus fungal.

Given these limitations, our retrospective design restricts causal inference, meaning we can only report associations, and all findings should be interpreted with caution.