4. Discussion
inflammation, death
COVID-19 PNEUMONIA, INFLAMMATION
The primary outcome clinical trial data of this study do not provide support for the use of anakinra in the treatment of severe CSS in COVID-19 pneumonia. The hypothesis underlying the study was that interleukin-1 receptor blockade in patients with COVID-19 would disrupt the cytokine storm and prevent the progression of the respiratory decline. The findings of this randomized, double-blind, placebo-controlled trial indicated that anakinra did not demonstrate a significant effect on the need for mechanical ventilation, death, the improvement in markers of inflammation (except for a nonsignificant improvement in CXCL9 levels, see below), or the need for supplemental oxygen. However, we found that a lower initial level of IL-6 predicted survival in this patient population. Given the small sample and the width of the confidence intervals in the efficacy comparisons, the possibility that treatment with anakinra may be associated with some clinical benefit or harm in certain patients cannot be excluded. The results reported herein vary from the conclusions drawn by several recent studies which suggested that interleukin-1 receptor blockade may have a positive effect on patients with COVID-19-associated CSS [Although not reaching statistical significance in the paired data analysis, the observation in our study that the CXCL9 levels trended lower among those treated with anakinra is noteworthy. CXCL9 is an interferon-gamma response gene and a recognized serum biomarker for increased IFN-γ production [Anakinra dosing and duration vary widely among the published studies. An observational study which demonstrated improvement in clinical outcomes with anakinra utilized substantially higher doses and for a longer duration to suppress inflammation [A major strength of this trial is its design as a double-blind randomized study of non-intubated patients with COVID-19-associated CSS. Our entry criteria were strict compared to those of most previous studies on COVID-19, regardless of the treatment explored. Despite the small sample size, the anakinra and placebo groups were well balanced according to baseline characteristics and additional treatments received during the study duration. Despite its strengths, this study has a few limitations. The explanation for the failure of anakinra to improve clinical outcomes in this trial is not clear. This study was conducted in a single center, which may limit the generalizability of our findings. This small study might be underpowered to detect statistically significant differences in intervention effects between groups. Appropriate sample sizes could not be accurately estimated when the trial was being planned near the onset of the COVID-19 pandemic. However, at the time of the study conceptualization, the in-hospital mortality was estimated to be approximately 80% among those admitted with CSS features. With the advent of routine dexamethasone use between the time of study conceptualization and submission for regulatory approvals and the start of enrollment, mortality was not as high as originally projected, and the study, as designed, became underpowered. It is possible that certain subgroup populations may nonetheless benefit from interleukin-1 receptor blockade using a different dose or duration with respect to those used in this study. This may be addressed in a larger randomized double-blind study. Lastly, the entry criteria were perhaps the strictest applied in any COVID-19 trial in regard to the requirement for presenting multiple features of CSS. Less stringent entry criteria, or using suPAR levels alone, may reveal the benefit of anakinra in treating hospitalized/hypoxic COVID-19 patients prior to the requirement for invasive mechanical ventilation [In summary, anakinra added to dexamethasone did not significantly impact patient outcomes in this study of patients with clinical laboratory features of severe CSS and mild-to-moderate COVID-19 pneumonia. Additional larger studies are needed to assess the efficacy, safety, timing, and optimal dosing and duration of anakinra treatment in select patients with more severe COVID-19 [