In a recent Cochrane Database of Systematic Reviews study, researchers assess the effectiveness and safety outcomes of interleukin-1 (IL-1) blocking agents in the treatment of coronavirus disease 2019 (COVID-19).
Study: Interleukin-1 blocking agents for treating COVID-19. Image Credit: Juan Gaertner / Shutterstock.com
Background
As of January 31, 2022, COVID-19, which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5.6 million deaths. While most individuals who are infected with SARS-CoV-2 will experience only mild clinical symptoms, a minority of COVID-19 patients will experience a severe form of the disease that is accompanied by a maladaptive hyperinflammatory response caused by the cytokine storm, which may lead to acute respiratory distress (ARDS) and death.
To mitigate the spread of SARS-CoV-2 and treat infected individuals, scientists have explored numerable approaches. In addition to the unprecedented development of vaccines against the SARS-CoV-2, many researchers have looked to repurpose a wide range of currently approved medications, including immune-modulatory treatments.
The potential of IL-1 blockers
Due to the cytokine storm that can arise during COVID-19, several potential treatment options may include either non-selective cytokine production inhibition through the use of corticosteroids or more targeted cytokine inhibitors. Among targeted cytokine inhibitors, IL-1 blocking agents have recently gained the interest of clinicians as a result of the key function of IL-1 in orchestrating the innate immune system response to tissue damage and viral infections.
IL-1 blockers are a cornerstone treatment for a broad spectrum of aberrant hyperinflammatory immune response syndrome, some of which include Still’s disease, macrophage activation syndrome, and cytokine release syndrome. IL-1 receptor blockers have also improved the survival rates in people who have sepsis with macrophage activation syndrome.
When IL-1 binds to its receptor, it triggers a cascade of inflammatory mediators, chemokines, and other cytokines. Early prevention of this binding and activation is hypothesized to prevent the ensuing escalation of the cytokine storm associated with COVID-19.
The three available IL-1 blockers include anakinra, which is an IL-1 receptor antagonist, canakinumab, which is a human anti-IL-1β monoclonal antibody, and rilonacept, which is an IL-1 blocker.
The current study aims to determine whether medications that block IL-1 are effective treatments for COVID-19 and if they cause any adverse effects. The authors of this study were particularly interested in assessing the impact of IL-1 blockers on the symptoms of COVID-19 patients and whether these agents improved mortality rates of this disease.
About the study
The present review is a sub-review of COVID-NMA, which is a living systematic review of all trials assessing treatment and preventive interventions for COVID-19. The reviewers searched online sources for randomized controlled trials (RCTs) of IL-1 blocking agents used to treat people with COVID-19. Out of the 48,043 references that were retrieved by searching electronic bibliographic databases, the reviewers found 699 references eligible for the full-text screening.
Study findings
The reviewers found six RCTs, of which included 2,132 people, that evaluated IL-1 blocking agents. To this end, four studies evaluated anakinra, and two evaluated canakinumab.
No RCTs using rilonacept were published or registered. All patients included in these six studies were hospitalized due to moderate or severe COVID-19, most of whom required oxygen supplementation.
Taken together, the six studies did not provide any evidence for a clinically relevant beneficial effect of IL-1 blocking agents in treating COVID-19. Several outcomes including clinical improvement, a World Health Organization (WHO) Clinical Progression score of 7 or above, all-cause mortality, incidence of any adverse events; and incidence of serious adverse events were assessed for all included studies. For each of these outcomes, the evidence was found to be uncertain or very uncertain.
Despite the conclusions made in the current study, it should be noted that anakinra is currently being assessed for treating children with COVID-19 in the Randomized Evaluation of COVID-19 Therapy (RECOVERY) platform.
Limitations
The authors of the current study expressed limited confidence in the evidence of the reviewed studies, as the patients involved in these studies were undergoing varied care and treatment in the hospital. Furthermore, most of these patients were seriously ill, some of whom were on ventilators. These studies also used different care and methods of measurement and reported their results using different methods.
Conclusions
The current review did not find sufficient evidence to demonstrate that IL-1 blocking agents are effective treatments for people with COVID-19 or whether these medications cause any unwanted side effects. Because of the inconclusive findings, the reviewers call for high-quality studies to evaluate the utility of IL-1 blocking agents to treat COVID-19.
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