Longitudinal assessment of IFN-I activity and immune profile in critically ill COVID-19 patients with acute respiratory distress syndrome

Abstract

Background: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved.

Methods: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements.

Results: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS.

Conclusions: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.

Keywords: ARDS; COVID-19; Immune profile; Immunosuppression; Type-I IFN.

Fig. 1

Correlation matrix of immune parameters at ICU admission. Immune parameters were measured at inclusion in 64 critically ill patients with COVID-19, and correlations were calculated using Spearman correlation tests. a Results are presented as a correlation matrix. Spearman correlation coefficients are plotted. Cells were colored according to the strength and trend of correlations (shades of red = positive, shades of green = negative correlations). Coefficients with a p value below 0.005 were highlighted in bold and considered significant after correction for multiple testing. Correlation results for non-independent parameters (i.e., lymphocyte subpopulations) are not presented. b Correlations between plasma interleukin-6 concentration at inclusion and sepsis-related organ failure (SOFA) score or PaO₂/FiO₂ ratio measured during first 24 h after admission are shown (n = 58). Corresponding logarithmic trendlines are shown

Fig. 2

Immune response in critically ill COVID-19 patients with or without ARDS. Immune parameters were measured three times (D0: within the first 48 h, D3: between day 3 and day 4, D7: between D7 and D9) during the first week after ICU admission in COVID-19 patients. Patients were split in two groups based on presence (n = 40) or not (n = 24) of acute respiratory distress syndrome (ARDS) during the first 72 h after admission according to Berlin definition. Over time evolution of immune parameters including plasma IFNα2 concentration and type I interferon mRNA signature (ISG score) during the first week after admission in patients with (blue boxes and circles) or without ARDS (orange boxes and circles) is shown. In one ARDS patient at D0 and in one ARDS patient at D7, plasma IFNα2 concentrations were null and could not be plotted. Correlation between plasma IFNα2 concentrations and type I interferon signatures is presented. Two values could not be plotted in the group of ARDS patients because measured IFNα2 concentrations were null. Data are presented as Tukey box-plots and individual values. Nonparametric Mann–Whitney test was used to compare values between groups at the same time point. Spearman correlation test was used. Spearman correlation coefficient is shown. Only p values below 0.05 are shown. The results were not adjusted for multiple test comparisons

Fig. 3

Immune response in COVID-19 ARDS patients according to status at D28. Immune parameters were measured 5 times (D0: within the first 48 h, D3: between day3 and D4, D7: between D7 and D9, D12: between D12 and D15, D20: between D20 and D25) during the first month after ICU admission in COVID-19 patients with ARDS. Patients were stratified in two groups according to their status at D28: survivors (n = 26) or non-survivors (n = 14). Over time evolution of immune parameters during the first month after admission in survivors (grey boxes) and non-survivors (red boxes) is shown. Regarding plasma IFNα2 level, in one non-survivor patient at D0 and in one survivor patient at D7, plasma IFNα2 concentration were null and could not be plotted. Data are presented as Tukey box-plots and individual values. Nonparametric Mann–Whitney test was used to compare values between groups at the same time point. Only p values below 0.05 are shown. The results were not adjusted for multiple test comparisons