Narrative review discusses paradoxical inflammatory reactions in pediatric patients receiving biologic therapy

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Frontiers in Medicine Published May 25, 2026 Medically reviewed May 25, 2026 DOI ↗ By Dr. Sofia Müller, MD · Lifespan & Whole-Person Care

Key Takeaway

Consider early recognition and severity-adapted management of flip-flop reactions in pediatric biologic therapy.

This narrative review addresses the topic of paradoxical inflammatory reactions in pediatric patients receiving biologic therapy. The authors synthesize the concept that paradoxical inflammation can represent a mechanistically consistent consequence of selective immune pressure rather than a coincidental adverse event. This perspective reframes the nature of these reactions within the context of biologic therapy use.

The review highlights that a unified mechanistic framework and practical clinical approach remain lacking, particularly in pediatric populations. This gap limits the ability to fully characterize the incidence or management of these events in this specific group. The authors emphasize that serious adverse events and discontinuations were not reported in the source material.

The practice relevance of this review is to support early recognition and severity-adapted management of flip-flop reactions. Clinicians should interpret these findings with caution given the absence of reported certainty and the lack of a standardized clinical approach for pediatric patients.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Paradoxical inflammatory reactions, also referred to as flip–flop phenomena, are increasingly recognized complications of biologic therapies targeting specific immune pathways. These reactions are characterized by the emergence of a new inflammatory phenotype with opposing immunologic polarization or by unexpected exacerbation of the underlying disease despite prior therapeutic response. Although numerous case reports have been published, a unified mechanistic framework and a practical clinical approach remain lacking, particularly in pediatric populations. In this narrative review, we synthesize current evidence on the immunopathogenesis of flip–flop reactions, focusing on dynamic interactions between the Th1/Th17, Th2, and interferon–JAK/STAT axes. We propose that paradoxical inflammation can represent a mechanistically consistent consequence of selective immune pressure rather than a coincidental adverse event. Five illustrative pediatric cases are presented as proof of concept, demonstrating distinct pathways leading to eczematous, psoriasiform, and interferon-driven phenotypes during biologic therapy. Based on mechanistic insights and clinical experience, we introduce a practical diagnostic and therapeutic algorithm designed to support early recognition and severity-adapted management of flip–flop reactions. Recognition of immune rebalancing as a therapeutic goal may facilitate rational treatment selection and improve outcomes in both pediatric and adult patients receiving biologic agents.