Anakinra authorized to treat severe coronavirus disease 2019; Sepsis breakthrough or time to reflect?

Abstract

IntroductionThe European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) announced conditions for using recombinant human interleukin-1 receptor antagonist (rhIL-1ra) to treat hospitalized patients with Coronavirus disease 2019 (COVID-19) and risk for progression. These decisions followed publication of the suPAR-guided Anakinra treatment for Validation of the risk and early Management OF seveRE respiratory failure by COVID-19 (SAVE- MORE) phase 3 clinical trial that yielded positive results.MethodsWe conducted a literature review and theoretical analysis of IL-1 blockade as a therapy to treat COVID-19. Using a stepwise analysis, we assessed clinical applicability of the SAVE-MORE results and evaluated conceptual support for interleukin-1 suppression as a suitable approach to COVID-19 treatment. This therapeutic approach was then examined as an example of inflammation-suppressing measures used to treat sepsis.ResultsAnakinra use as a COVID-19 therapy seems to rely on a view of pathogenesis that incorrectly reflects human disease. Since COVID-19 is an example of sepsis, COVID-19 benefit due to anti-inflammatory therapy contradicts an extensive history of unsuccessful clinical study. Repurposing rhIL-1ra to treat COVID-19 appears to exemplify a cycle followed by inflammation-suppressing sepsis treatments. A landscape of treatment failures is interrupted by a successful clinical trial. However, subsequent confirmatory study fails to replicate the positive data.DiscussionWe suggest further experimentation is not a promising pathway to discover game-changing sepsis therapies. A different kind of approach may be necessary.

Revolution in sepsis: a symptoms-based to a systems-based approach?

“…Today, fluid resuscitation may cause harm to some patients. Contrary to its name, normal saline is not normal, and the volumes and timings are not effective in critically ill patients [ 11 , 16 , 108 , 121 , 149 , 150 ]. Large aggressive fluid volumes create dilutional coagulopathy, fluid overload, and pathogenic pulmonary and tissue edema, acute kidney injury, prolonged ICU stays and higher mortality [ 55 , 108 , 149 , 150 ].…”

“…Contrary to its name, normal saline is not normal, and the volumes and timings are not effective in critically ill patients [ 11 , 16 , 108 , 121 , 149 , 150 ]. Large aggressive fluid volumes create dilutional coagulopathy, fluid overload, and pathogenic pulmonary and tissue edema, acute kidney injury, prolonged ICU stays and higher mortality [ 55 , 108 , 149 , 150 ]. If normal saline was evaluated today by the European, USA and Australian regulatory bodies, there is a high chance it was not be approved for human use .…”

“…The harmful effects of normal saline solutions were recognized over 100 years ago by George Evans when he wrote in 1911 : “ One cannot fail to be impressed with the danger of such procedure, if one observes the utter recklessness with which salt solution is frequently prescribed, particularly in the postoperative period, without previous knowledge of the condition of blood pressure, the ability of the heart to handle large amounts of fluid successfully, or the functional capacity of the kidneys to excrete the large amount of chloride thus formed on them ” [ 5 , 57 ]. More recently, vasopressor agents that increase cardiac contractility or vasoconstriction have also come under clinical scrutiny that include increased cardiac workload, arrhythmias and vasoconstriction-related tissue ischemia [ 149 , 150 ].…”

“… Clinical study of antiinflammation strategies to treat sepsis has been characterized by a predictable cycle of abundant clinical failures punctuated by an intermittent positive result. Shapiro and colleagues (2023) [ 149 , 150 ] …”

“…Individualized treatments have also progressed in the chronic, immunosuppressive stage of sepsis responsible for later-stage morbidity and mortality [ 143 ]. Notwithstanding these advances, there remains few safe and effective drugs for the early treatment of sepsis [ 92 , 102 , 103 , 149 , 149 , 150 , 150 ]. For example, there are only a handful of drugs to reduce excessive inflammation and immune dysfunction.…”