Resolution Signals in Recurrent Fever: Mechanisms, Clinical Implications, and Advances

Abstract

Recurrent fever syndromes are a complex and heterogeneous group of disorders that often pose diagnostic and therapeutic challenges for clinicians. The identification and understanding of resolution signals—molecular and cellular mechanisms that actively terminate febrile episodes—are critical for optimizing management and improving patient outcomes. This review synthesizes current knowledge on the epidemiology, pathophysiology, and clinical implications of resolution signals in recurrent fever, integrating recent advances and guideline-based recommendations for effective diagnosis and management.

Introduction

Recurrent fever represents a significant diagnostic dilemma in clinical practice, particularly in pediatric and immunocompromised populations. Defined by repeated episodes of elevated body temperature separated by periods of normothermia, recurrent fever can result from autoinflammatory, infectious, malignant, or autoimmune etiologies. While much focus has been placed on the triggers and propagation of fever, less attention has been paid to the mechanisms underlying its resolution. Understanding these resolution signals is vital for the comprehensive care of patients and the development of targeted therapies.

Epidemiology / Disease Burden

The global epidemiology of recurrent fever syndromes varies with underlying etiology. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, familial Mediterranean fever (FMF), and other hereditary periodic fever syndromes primarily affect children, with estimated prevalences ranging from 2 to 10 per 100,000 individuals for FMF in endemic areas. Infectious causes, especially in immunocompromised hosts, remain prevalent in both pediatric and adult populations. The recurrent nature of these fevers leads to significant morbidity, healthcare utilization, and negative impacts on quality of life. Timely identification of resolution mechanisms may help reduce disease burden and improve long-term outcomes.

Pathophysiology

The pathophysiology of recurrent fever involves cyclical activation and resolution of the inflammatory response. Central to the resolution phase are specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins. These lipid-derived molecules actively promote the cessation of inflammation by inducing apoptosis of neutrophils, enhancing efferocytosis by macrophages, and suppressing pro-inflammatory cytokine production. Additionally, regulatory T cells (Tregs) and anti-inflammatory cytokines such as IL-10 and TGF-β play essential roles in restoring immune homeostasis. In hereditary periodic fever syndromes, genetic mutations often result in dysregulated inflammasome activity, leading to recurrent inflammatory episodes. The failure or delay in resolution signals can perpetuate fever and tissue damage, thus highlighting their clinical significance.

Risk Factors

Risk factors for recurrent fever syndromes include genetic predispositions—such as mutations in MEFV, TNFRSF1A, MVK, and NLRP3 genes—immunodeficiency states, chronic infections, and exposure to environmental triggers or stressors. Patients with a family history of autoinflammatory diseases or consanguinity are at increased risk. Immunosuppressive therapies and malignancies may also compromise the ability to mount or resolve fever responses. Recognition of these risk factors is essential for early diagnosis and tailored management.

Clinical Features

Recurrent fevers typically present as stereotypical episodes of fever lasting from hours to days, separated by symptom-free intervals. Associated features depend on the underlying disorder and may include rash, arthralgia, abdominal pain, mucosal ulcers, lymphadenopathy, and serositis. In PFAPA, episodes are accompanied by aphthous stomatitis, pharyngitis, and cervical adenitis. FMF is characterized by serosal inflammation and erysipelas-like skin lesions. The interval, duration, and associated symptoms provide diagnostic clues and may reflect the underlying efficiency or deficiency of resolution signals.

Diagnosis

Diagnostic evaluation of recurrent fever requires a thorough clinical history, focusing on episode pattern, associated symptoms, family history, and response to treatment. Laboratory investigations should include inflammatory markers (CRP, ESR), complete blood count, and targeted genetic testing where indicated. Exclusion of infectious, malignant, and autoimmune etiologies is critical. Recent advances in immunological assays allow for the assessment of SPMs and cytokine profiles, providing insight into resolution pathways and guiding personalized therapy. Diagnostic criteria for periodic fever syndromes have been refined in recent guidelines, aiding in standardization of diagnosis.

Treatment & Management

Management strategies aim to control febrile episodes, prevent complications, and restore quality of life. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids remain mainstays for acute episode control. Colchicine is effective in FMF and some other hereditary syndromes, reducing attack frequency and amyloidosis risk. Biologic agents targeting IL-1 (anakinra, canakinumab) or TNF-α (etanercept) are reserved for refractory cases or specific syndromes such as TRAPS and CAPS. Supportive care and patient education are integral to long-term management. Recognition and modulation of resolution signals, including the potential use of SPM analogs, represent emerging therapeutic avenues.

Recent Advances / Emerging Therapies

Recent research has focused on harnessing endogenous resolution mechanisms for therapeutic benefit. Experimental studies highlight the efficacy of SPM analogs in reducing inflammation without immunosuppression, preserving host defense while actively promoting resolution. Advances in genomic profiling and cytokine monitoring have enabled precision medicine approaches, tailoring therapy to individual inflammatory profiles. Clinical trials are underway to evaluate novel agents that enhance efferocytosis and modulate inflammasome activity, offering promise for patients with refractory recurrent fever syndromes.

Guideline Recommendations

Guidelines from the Eurofever Project and the American College of Rheumatology emphasize early diagnosis, regular monitoring for complications (e.g., amyloidosis in FMF), and individualized therapy based on genetic and clinical features. Colchicine remains first-line therapy for FMF, with biologics indicated for colchicine-resistant or other autoinflammatory syndromes. The importance of monitoring resolution markers, patient-reported outcomes, and adherence is increasingly recognized in clinical practice. Multidisciplinary management is recommended for complex cases, involving rheumatologists, immunologists, and geneticists.

Conclusion

The elucidation of resolution signals in recurrent fever syndromes has advanced our understanding of disease mechanisms and opened the door to novel therapeutic strategies. Early recognition of deficient or delayed resolution is crucial for optimizing management and preventing complications. Ongoing research into SPMs, genetic determinants, and targeted therapies holds promise for improved outcomes in this challenging patient population. Integration of guideline-based recommendations with emerging scientific insights will continue to refine the care of patients with recurrent fever, ultimately reducing disease burden and enhancing quality of life.