Study population and setting
This study enrolled consecutive patients with COVID-19 in an Italian hospital who had moderate-to-severe acute respiratory distress syndrome and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both). Patients were not intubated or in the ICU at the time of enrollment. All had received standard of care therapy, including 200 mg hydroxychloroquine twice a day orally, and 400 mg lopinavir with 100 mg ritonavir twice a day orally. The authors compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in patients who received treatment with high-dose anakinira (an interleukin [IL]-1 inhibitor) or low-dose anakinra, to a retrospective cohort of patients who did not receive anakinra.
Summary of Main Findings
29 patients received high-dose intravenous anakinra, seven patients received low-dose subcutaneous anakinra (in this group anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein (CRP) and clinical status), and 16 patients received the standard of care therapy. Recipients of high-dose anakinra were slightly older than the standard of care group. CRP and ferritin levels were slightly higher in the standard therapy group than among high-dose anakinra recipients. PaO2:FiO2 were higher in the standard of care group than in the high-dose anakinra group. At 21 days of follow-up, in the high-dose anakinra group five (17%) patients were on mechanical ventilation and three (10%) died. In the standard of care group one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard of care group (p=0009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard of care group (p=0.015).
It is plausible to consider use of an IL-1 inhibitor to address the malignant effects of the cytokine release syndrome that has been described in people with moderate to severe COVID-19. The absence of CRP decline in the low-dose anakinra group, in contrast to the presence of CRP declines in the high-dose anakinra group, gives some suggestion of a dose-effect.
As this is a retrospective cohort study it is challenging to limit the bias that patients who were given high-dose anakinra were also given other treatments that improved their outcomes. Baseline CRP and ferritin levels in the standard therapy group suggest that these patients had more inflammation, while the lower PaO2:FiO2 ratio in high-dose anakinra recipients indicates that they had greater ventilator defects. Sample sizes were also quite small, and the authors do not state how the use of anakinra was determined (clinician discretion, criteria, etc). The authors use historical controls, treated 7-10 days prior to the anakinra group. Since the historical controls were not too removed in time from the anakinra group, they can be considered similar, but this may not account for major changes in hospital and treatment practice that may have accompanied the addition of anakinra which could have led to different outcomes. In addition, although selection criteria included elevated CRP and ferritin, these markers are not strictly and only in the signaling pathway of IL-1. Although IL-1 is difficult to detect in plasma, it is possible that some anakinra recipients may not have had enhanced IL-1 signaling (and thus would not have benefitted from anakinra). It is also unclear whether persons who received IL-6 inhibitors were excluded, which may have impacted the cytokine release syndrome in COVID-19. Importantly, the differences in CRP trajectories between the high-dose anakinra group and the standard treatment group are not readily apparent, and the authors provide no analysis to justify any differences.
First report of anti-IL-1 inhibitor for treatment in patients with COVID-19.