Hereby, we report the use of anakinra in eight patients with acute fulminant myocarditis and its benefit on LV function recovery. The possible outcomes of myocarditis in children are sudden death, arrhythmias, myocardial infarcts and heart failure with dilated cardiomyopathy phenotype [1]. An analysis of the Pediatric Cardiomyopathy Registry (PCMR), including 369 children with myocarditis, found that 3 years after presentation approximately 7% of patients had died, 18% had undergone heart transplantation and 53% had normal left ventricular structure and systolic function [10]. In the current case series none of the patient died or were transplanted. All of them had achieved echocardiographic normalization and only two of six children had arrhythmia. Profibrotic cytokines including interleukin IL-1β play an essential role in tissue remodeling by stimulating fibroblast proliferation resulting in greater collagen synthesis and fibrosis [11]. In adults with acute myocarditis, formation of the inflammasome is a well-recognized pathogenic mechanism. Inflammasomes are a group of protein complexes which recognize a diverse set of inflammation-inducing stimuli, including Pathogen- and Damage-Associated Molecular Patterns, and control the production of several proinflammatory cytokines, such as IL-1β [6]. The use of early IL-1 receptor antagonist in patients identified with an inflammatory cardiomyopathy might further reduce progression to chronic dilated cardiomyopathy. In our series, all patient had high C-reactive protein suggestive of significant systemic inflammatory process. A randomized study in adults is currently underway comparing anakinra versus placebo for the treatment of acute myocarditis (ARAMIS, ClinicalTrials.gov Identifier: NCT03018834). Anakinra is a recognized therapy targeting the inflammasome in various systemic inflammatory disease, such as rheumatoid arthritis and juvenile polyarthritis [9]. In children, it is a therapy under investigation for Kawasaki disease that shows many clinical similarities with MIS-C [12, 13]. In our series, in most patients LVEF improvement was noted in the first hours following anakinra injection. The effect of other treatments such as corticosteroids cannot be excluded. Effect of IVIg is questionable. A systematic review of IVIg therapy in presumed viral myocarditis included only one randomized pediatric study of 86 children and found that IVIg did not significantly improve survival or left ventricular function [14]. Three patients did not hemodynamically tolerate large volume load secondary to IVIg infusion and treatment was interrupted. Altogether, currently neither corticosteroids nor IVIg ever showed such immediate recovery of contractile function during acute fulminant myocarditis. As for the treatment of MIS-C, use of IVIg, glucocorticoids, showed conflicting results. The US Overcoming Covid consortium [15] determined that initial treatment of MIS-C with immunoglobulin plus glucocorticoids was associated with a lower risk of cardiovascular dysfunction, requirement of adjunct therapies and vasopressors than with IVIg alone. In contrast, the international Best Available Treatment Study (BATS) consortium found no statistically significant difference for ventilation, inotropic support, death or for improvement on an ordinal clinical severity scale for any of the three treatments: immunoglobulin alone, a combination of immunoglobulin and glucocorticoids, or glucocorticoids alone [16]. This discrepency may be explained by different patient severity, different SARS-CoV-2 variants, but neither of these studies definitively answered the question about effective single or combination of immunomodulatory treatment including steroids, IVIg and biotherapies with monoclonal antibodies, such as anakinra and infliximab [17]. Although it is becoming increasingly clear that rapid immunomodulatory therapies can be lifesaving in patients with MIS-C, the underlying change in the therapeutic paradigm of acute fulminant myocarditis is changing and warrant randomized, controlled trials to evaluate the safety and efficacy of biotherapies in acute myocarditis.
In conclusion, our retrospective case series supports further investigation of the role for IL-1 receptor antagonist in the treatment of pediatric acute and fulminant myocarditis. All patients had rapid response to anakinra on contractile dysfunction and cardiac enzymes. Given its safety [18] and rapid onset of action, anakinra may have a place in the pediatric myocarditis treatment.
