In this ancillary study of the coVAPid study, we found no significant association between corticosteroid adjuvant therapy and the incidence of VA-LRTI in a population of SARS-CoV-2 patients invasively ventilated for over 48 hours. However, we found a significant time-varying effect of corticosteroid adjuvant therapy on the incidence of VA-LRTI over the 28-day period.
In this study, the incidence of VA-LRTI in the SARS-CoV-2 population was high with half of the patients presenting at least one VA-LRTI during ICU-stay, irrespective of their corticosteroid use. This is in line with several previous studies that described the high incidence of VA-LRTI in critically-ill COVID-19 patients [3, 8–10, 17].
Corticosteroid-adjuvant administrations for SARS-CoV-2 patients dramatically increased in the ICU following the RECOVERY trial, although only 15% patients were invasively ventilated in this trial. In the SARS-CoV-2 population invasively ventilated, high rates of ARDS, prolonged ICU stay and IMV duration along with immunologic disorders and neuromuscular blocking agent use, expose these patients to higher risk of developing VA-LRTI and one could question the impact of wide prescription of corticosteroids on the incidence of hospital-acquired infections (HAI) and VA-LRTI in this population, already at higher risk for acquired infections.
VA-LRTI in COVID-19 patients is a serious issue, as our group and others demonstrated a significant association between VA-LRTI and mortality in this population [24, 25]. However, to date there is no prospective interventional study that evaluated the impact of corticosteroid exposure on the incidence of VA-LRTI as the RECOVERY study itself did not include it as an outcome.
There is a growing body of evidence in the literature pointing out the increased risk of developing VA-LRTI in COVID-19 patients treated with corticosteroids [16–19].
A recent study by Mesland et al. [17] demonstrated among 322 COVID-19 patients invasively ventilated a significantly higher incidence for VA-LRTI in patients receiving corticosteroid adjuvant therapy and corticosteroids were found to be an independent factor associated with VA-LRTI in a multivariable adjusted analysis. Another study found the same association between corticosteroid and VA-LRTI [18] but these results are conflicting with other data suggesting no association between corticosteroid exposure and the incidence of VA-LRTI in patients invasively ventilated for a severe SARS-CoV-2 pneumonia [15, 26].
In our study we did not demonstrate a significant association between corticosteroid exposure and VA-LRTI incidence during the 28-day follow-up, but we demonstrated for the first time a time varying effect of corticosteroid exposure on the incidence of VA-LRTI. We found the effect of corticosteroid exposure on the incidence of VA-LRTI was varying through time with an increased association all along the 28-day follow-up. This association became statistically significant after the 14th day of mechanical ventilation.
Several factors may explain this time varying effect between corticosteroid exposure and the incidence of VA-LRTI. First, corticosteroid-immunosuppressive effect is a time-dependent but also a cumulative-dose-dependent mechanism [27] that may explain the late occurrence of hospital acquired infections in treated patients. Second, sepsis-associated immunosuppression is a time-dependent process that could add itself to the corticosteroid immunosuppressive effect with immunoparalysis occurring in the late course of ICU stay promoting HAI [28, 29]. Finally, SARS-CoV-2 mediated immune dysfunction is associated with a progressive lymphopenia [30, 31] and a multifactorial immunosuppression culminating after day 14 [32] that exposes patients to late onset of HAI and VA-LRTI.
Our study report higher 28-day mortality and longer MV duration in the group of patients exposed to corticosteroid adjuvant therapy as compared to those who did not. The main reason for this discrepancy with results of randomized controlled trials [13, 33]might be the observational design of this study taking place before the RECOVERY era when corticosteroid prescriptions were at the discretion of attending physicians who selected the sickest patients to receive these treatments. Septic shock, non-resolving ARDS and intense systemic inflammation were the main reasons for corticosteroid-adjuvant therapy and this led de facto to a poorer prognosis in the corticosteroid-treated patients. Several other observational studies also failed to demonstrate this benefit from corticosteroids [17, 33].
Microorganisms responsible for VAP in our study did not differ among the corticosteroid treated and non-treated patients. In line with previous results, Gram-negative bacilli were the main bacteria found in respiratory tract samples with a high rate of Enterobacteriaceae and Pseudomonas aeruginosa. Methicillin-sensitive Staphylococcus aureus was the main Gram-positive cocci, and the rate of multidrug-resistant bacteria was also high [3, 15, 17].
To our knowledge, our study with 545 patients included all around Europe is the largest multicenter study to examine the impact of corticosteroid adjuvant therapy on the incidence of VA-LRTI in a population of invasively ventilated patients for SARS-CoV-2 infection and the first to demonstrate the varying association of corticosteroid exposure on the incidence of VA-LRTI throughout time. Additional strengths of our study are the large number of patients, the multicenter design and the strict definition of VA-LRTI with microbiological documentation for each event. However, some limitations need to be mentioned. First, the observational retrospective design of our study taking place before the RECOVERY era is responsible for possible selection bias with disparate use of corticosteroids among centers that intentionally selected the sickest patients to receive corticosteroids, naturally leading to poorer outcomes. Second, a minority of included patients (30%) were receiving corticosteroids, which could also introduce a selection bias. Third, in our study we registered all steroid prescriptions irrespective of variations in molecule, duration and dosage. The impact of this discrepancy on the patient outcomes might be real, yet no data support this in the literature.