Comment on “Massive idiopathic pericardial effusion in a pediatric patient responsive to interleukin-1 receptor antagonist: Unveiling an undercover hyperinflammation?”

Dear Editor,

We read with great interest the recently published article by Pasquinucci et al. describing the successful treatment of massive chronic idiopathic pericardial effusion with anakinra in a pediatric patient.[1] The case is undoubtedly clinically intriguing and contributes valuable observations regarding the possible role of cytokine profiling in selected patients with refractory pericardial disease. In particular, the markedly elevated pericardial interleukin-6 (IL-6) levels despite the absence of overt systemic inflammatory findings represent a noteworthy and hypothesis-generating observation. Nevertheless, we believe that several aspects of the proposed pathophysiological interpretation merit further consideration.

Although the markedly elevated pericardial IL-6 level is an important finding, it may not necessarily represent specific evidence of IL-1-mediated autoinflammation.[2] IL-6 is a pleiotropic cytokine implicated in numerous inflammatory states and has been associated with increased endothelial permeability and fluid accumulation.[2] Therefore, in the setting of massive pericardial effusion, elevated IL-6 may represent a driver, amplifier, or even a consequence of local pericardial inflammation rather than a reliable upstream marker of IL-1α-dominant disease. In this regard, the proposed mechanistic link between isolated IL-6 elevation and occult IL-1-mediated hyperinflammation may remain speculative.

An additional point deserving attention is the apparent mismatch between the reported clinical phenotype and the evidence base supporting IL-1 blockade. Most studies evaluating anakinra in pericardial disease have focused on patients with overt inflammatory recurrent pericarditis characterized by chest pain, elevated inflammatory markers, corticosteroid dependence, and colchicine resistance.[3] In contrast, the present patient reportedly lacked typical features of active inflammatory pericarditis, remained largely asymptomatic for prolonged periods, and exhibited persistently normal systemic inflammatory markers. Although the observed response is clinically noteworthy, extrapolating therapeutic paradigms from inflammatory recurrent pericarditis to isolated chronic pericardial effusion may require additional caution.

Furthermore, the sustained remission observed after anakinra (recombinant IL-1 receptor antagonist) initiation should be interpreted carefully. The patient simultaneously received colchicine, which modulates inflammasome activation through mechanisms distinct from IL-1 receptor blockade and has been shown to enhance recurrence prevention when combined with anakinra in recurrent pericarditis.[4] Therefore, the clinical response cannot be considered specific evidence of an IL-1α-driven disease process. Alternative explanations, including synergistic anti-inflammatory effects, prolonged drainage-related stabilization, or the fluctuating natural history of chronic pericardial effusion, remain plausible.

The recent 2025 European Society of Cardiology (ESC) guidelines and the 2024–2025 American College of Cardiology (ACC) consensus documents position IL-1 blockade primarily within the management of inflammatory and refractory recurrent pericarditis.[5] In particular, ACC guidance appears to favor corticosteroid-based approaches in noninflammatory phenotypes characterized by normal C-reactive protein levels, whereas ESC recommendations emphasize IL-1 inhibitors mainly after failure of standard triple therapy (nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids) while also emphasizing the importance of cost-effectiveness and careful therapeutic escalation.[5] In this context, extending biologic therapy to isolated chronic pericardial effusion without overt systemic inflammation appears highly interesting, but may warrant further clarification regarding phenotype definition and therapeutic sequencing.

Despite these considerations, we believe that the authors should be commended for reporting a rare and thought-provoking pediatric case that broadens the ongoing discussion regarding localized inflammatory pathways in pericardial disease. The report importantly highlights the potential value of integrating cardiologic and immunologic perspectives in complex pericardial disorders and may encourage future studies aimed at better defining the role of cytokine profiling and biologic therapies in selected patients with chronic pericardial effusion.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.