Innate Immune Memory in Recurrent Fever: Mechanisms, Clinical Insights, and Therapeutic Implications

Abstract

Recurrent fever syndromes are a diagnostic and therapeutic challenge in clinical practice, often linked to complex interactions within the innate immune system. Recent advances have highlighted the concept of innate immune memory, known as trained immunity, as a pivotal mechanism in the pathogenesis and perpetuation of these syndromes. This review synthesizes current evidence on the epidemiology, pathophysiology, and clinical presentation of recurrent fever with a focus on innate immune memory, underscoring recent advances and guideline-directed management. The article aims to equip clinicians with mechanistic insights and practical considerations for optimizing patient outcomes in the context of recurrent fever syndromes.

Introduction

Recurrent fever syndromes encompass a heterogeneous group of disorders characterized by episodic febrile episodes without identifiable infectious triggers. While historically attributed to dysregulation of the adaptive immune system or hereditary periodic fever syndromes, emerging research has redefined our understanding—pointing toward the role of the innate immune compartment in mediating these events. The phenomenon of innate immune memory, or trained immunity, describes the capacity of innate immune cells to mount an enhanced or maladaptive response upon re-exposure to certain stimuli, shaping the landscape of recurrent fever pathogenesis. This review integrates the latest scientific knowledge to provide a comprehensive overview for healthcare professionals managing patients with recurrent fever.

Epidemiology / Disease Burden

Recurrent fever syndromes represent a significant clinical burden, particularly in pediatric populations but also increasingly recognized in adults. The prevalence varies by geographic region, genetic background, and underlying etiology. Hereditary autoinflammatory syndromes, such as Familial Mediterranean Fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS), are notable examples. However, non-monogenic and idiopathic recurrent fevers are also common, often underdiagnosed due to overlapping clinical features and lack of awareness. The morbidity associated with recurrent fever stems from repeated healthcare utilization, diagnostic uncertainty, impact on quality of life, and the risk of long-term sequelae such as amyloidosis in untreated cases.

Pathophysiology

Traditionally, recurrent fevers were attributed to adaptive immunity or monogenic defects in inflammasome regulation. Recent studies, however, have brought innate immune memory to the forefront. Trained immunity refers to a functional reprogramming of innate immune cells—such as monocytes, macrophages, and NK cells—following exposure to microbial patterns or endogenous danger signals. This process is mediated by epigenetic modifications, metabolic rewiring, and altered cytokine responses, enabling these cells to respond more robustly or aberrantly upon subsequent encounters. In recurrent fever syndromes, inappropriate or exaggerated trained immunity may underlie the periodic activation of pro-inflammatory pathways, particularly the interleukin-1 (IL-1) axis. This can occur independently of adaptive immune triggers and may be initiated by infectious, sterile, or metabolic stimuli, perpetuating a cycle of fever and systemic inflammation.

Risk Factors

Risk factors for recurrent fever syndromes with an innate immune memory component include genetic mutations (e.g., MEFV, NLRP3, TNFRSF1A), a history of severe infections or repeated microbial exposure, dysbiosis, and environmental factors such as chronic stress or metabolic syndrome. Epigenetic predispositions and alterations in host-microbiome interactions may also prime innate immune cells for maladaptive trained responses. In some cases, therapeutic interventions or vaccination can transiently modulate innate immune memory, either protecting against or predisposing individuals to recurrent inflammatory episodes.

Clinical Features

Patients typically present with self-limited episodes of high-grade fever, often accompanied by systemic manifestations such as malaise, myalgia, arthralgia, abdominal pain, rash, serositis, and lymphadenopathy. The periodicity and associated symptoms can vary considerably, with some syndromes demonstrating clockwork regularity and others displaying more erratic patterns. Laboratory findings during attacks commonly reveal elevated acute phase reactants (CRP, ESR, SAA), leukocytosis, and sometimes neutrophilia. Inter-episode periods are generally asymptomatic, but subclinical inflammation may persist in some cases, contributing to long-term complications.

Diagnosis

The diagnosis of recurrent fever syndromes requires a high index of suspicion and detailed clinical history, including age of onset, family history, ethnicity, and attack characteristics. Laboratory workup should exclude infectious, autoimmune, and malignant etiologies. Genetic testing is warranted in suspected hereditary cases but may not explain all presentations. Recent research highlights the potential utility of assessing innate immune function, cytokine profiles (notably IL-1β, IL-6, TNF-α), and epigenetic markers indicative of trained immunity, though these remain largely investigational. Diagnostic criteria from international expert panels (e.g., Eurofever, PRINTO) provide helpful frameworks but may not capture all cases, underscoring the need for individualized assessment.

Treatment & Management

Management of recurrent fever syndromes is tailored to the underlying etiology and severity. In monogenic autoinflammatory disorders, targeted therapies such as colchicine (FMF), IL-1 inhibitors (anakinra, canakinumab), and anti-TNF agents (TRAPS) are mainstays. For non-monogenic or idiopathic cases, empirical anti-inflammatory agents, corticosteroids, or biologics may be considered. Understanding the role of innate immune memory opens new avenues for personalized therapy—potentially including agents targeting epigenetic modifications or metabolic pathways involved in trained immunity. Supportive care, patient education, and regular monitoring for complications remain integral components of management.

Recent Advances / Emerging Therapies

Recent years have witnessed significant progress in delineating the molecular underpinnings of trained immunity in recurrent fever. Novel agents targeting upstream regulators of innate immune memory, such as bromodomain inhibitors (targeting epigenetic readers) and metabolic modulators (e.g., mTOR inhibitors, statins), are under investigation. Advances in single-cell sequencing and multi-omics have improved our ability to phenotype patients and predict therapeutic response. Early-phase clinical trials are exploring the safety and efficacy of these precision therapies, which may fundamentally alter the course of refractory cases. The integration of artificial intelligence and machine learning into clinical practice is also enhancing pattern recognition and risk stratification.

Guideline Recommendations

Current guidelines from the European League Against Rheumatism (EULAR), American College of Rheumatology (ACR), and international autoinflammatory disease consortia emphasize the importance of early diagnosis, genetic counseling, and targeted therapy in recurrent fever syndromes. Regular monitoring for amyloidosis and organ dysfunction is recommended, alongside patient education regarding disease course and treatment adherence. Emerging guidelines are beginning to incorporate considerations related to innate immune memory, especially in the context of novel biomarkers and therapeutic strategies.

Conclusion

Innate immune memory represents a paradigm shift in our understanding of recurrent fever syndromes, bridging the gap between genetic predisposition, environmental triggers, and clinical phenotype. Mechanistic insights into trained immunity are offering new diagnostic and therapeutic opportunities, with the potential to transform patient outcomes. Continued research, multidisciplinary collaboration, and adherence to evolving guidelines are essential for optimizing care in this complex and dynamic field.