Host Metabolic States in Recurrent Fever: Mechanisms, Clinical Implications, and Emerging Therapeutic Strategies

Abstract

Recurrent fever syndromes represent a diagnostic and therapeutic challenge in clinical practice, often reflecting a spectrum of underlying autoinflammatory, infectious, or metabolic disorders. Recent advances underscore the pivotal role of host metabolic states in shaping susceptibility, disease expression, and therapeutic responsiveness in patients with recurrent fever. This review synthesizes current evidence on the epidemiology, mechanisms, clinical features, diagnostic workup, and management of recurrent fever, emphasizing the interplay between metabolic pathways and immune regulation. Key insights into risk stratification, emerging therapies, and guideline-based recommendations are provided to inform contemporary clinical practice.

Introduction

Recurrent fever syndromes encompass a heterogeneous group of disorders characterized by repeated episodes of elevated body temperature, often accompanied by systemic inflammation and variable organ involvement. These syndromes may be monogenic or multifactorial, and their pathogenesis frequently involves dysregulated host immune responses, with metabolic states playing a critical role in modulating inflammation. Understanding the intricate relationship between metabolism and immune activation is crucial for the effective management of recurrent fever, particularly as novel therapeutic targets emerge from this intersection.

Epidemiology / Disease Burden

Recurrent fever is encountered across age groups, with higher prevalence in pediatric populations due to inherited periodic fever syndromes such as Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), and Mevalonate Kinase Deficiency (MKD). In adults, recurrent fever may signal underlying autoimmune, infectious, or neoplastic conditions. Epidemiological studies suggest that up to 10% of children presenting to tertiary care with recurrent fever have an identifiable autoinflammatory syndrome, while the true global burden remains underestimated due to diagnostic challenges and under-recognition, especially in resource-limited settings.

Pathophysiology

The pathogenesis of recurrent fever is multifactorial, often involving genetic predisposition, environmental triggers, and aberrant immune-metabolic interactions. Central to these processes is the activation of inflammasome pathways, leading to excessive interleukin-1β (IL-1β) and interleukin-6 (IL-6) production. Host metabolic states, including obesity, insulin resistance, and mitochondrial dysfunction, have been shown to amplify pro-inflammatory signaling, thereby increasing the frequency or severity of fever episodes. Metabolic intermediates such as succinate, lactate, and free fatty acids serve as danger-associated molecular patterns (DAMPs), perpetuating innate immune activation. Moreover, alterations in lipid and glucose metabolism directly impact neutrophil, macrophage, and lymphocyte function, further modulating disease expression.

Risk Factors

Risk factors for recurrent fever extend beyond genetic mutations to encompass acquired metabolic derangements. Obesity, metabolic syndrome, and poorly controlled diabetes mellitus are associated with heightened systemic inflammation and increased risk for autoinflammatory episodes. Chronic infections, malignancy, and certain medications can also disrupt immune-metabolic homeostasis, predisposing individuals to recurrent febrile events. In pediatric populations, consanguinity and positive family history are notable risk factors for monogenic periodic fever syndromes.

Clinical Features

Patients with recurrent fever typically present with episodic high-grade fever lasting several days, interspersed with asymptomatic intervals. Accompanying symptoms may include arthralgias, myalgias, abdominal pain, rash, lymphadenopathy, and mucosal ulcers. The pattern, duration, and associated features of fever episodes can provide important diagnostic clues. For example, FMF often presents with serositis and erysipeloid rash, while TRAPS is characterized by migratory erythema and periorbital edema. Metabolic comorbidities such as obesity may exacerbate fever severity and frequency, and may be associated with longer disease duration and increased risk for amyloidosis in certain syndromes.

Diagnosis

The diagnosis of recurrent fever is predicated upon careful clinical assessment, supported by laboratory and genetic investigations. Routine workup includes complete blood count, inflammatory markers (CRP, ESR), liver and renal function tests, and cultures to exclude infection. Genetic testing may be warranted in cases with suggestive clinical features or family history. Metabolic evaluation, including assessment of glucose, lipid profile, and markers of mitochondrial function, is increasingly recognized as important in patients with unexplained or refractory fever. Diagnostic criteria such as the Eurofever/PRINTO classification assist in standardized diagnosis of autoinflammatory syndromes.

Treatment & Management

Management of recurrent fever is tailored to the underlying etiology and patient-specific risk factors. Colchicine remains the mainstay for FMF, whereas IL-1 inhibitors (anakinra, canakinumab) and TNF inhibitors are indicated for other autoinflammatory syndromes with metabolic involvement. Optimization of metabolic health through weight management, glycemic control, and treatment of dyslipidemia is increasingly emphasized as an adjunct to immunomodulatory therapy. Supportive care, including antipyretics and hydration, is essential during acute episodes. Multidisciplinary collaboration is often required for complex or refractory cases.

Recent Advances / Emerging Therapies

Recent research has highlighted the therapeutic potential of targeting metabolic pathways in recurrent fever syndromes. Agents that modulate glycolysis, fatty acid oxidation, or mitochondrial function are under investigation as adjuncts to immunosuppressive therapy. Clinical trials evaluating SGLT2 inhibitors, metformin, and mitochondrial antioxidants in autoinflammatory diseases have demonstrated preliminary efficacy in reducing fever frequency and systemic inflammation. The advent of next-generation sequencing has improved the identification of novel genetic and metabolic biomarkers, enabling personalized medicine approaches and earlier intervention.

Guideline Recommendations

Current guidelines from the European League Against Rheumatism (EULAR) and other expert bodies emphasize the importance of early recognition, genetic confirmation, and regular monitoring for complications such as amyloidosis in recurrent fever syndromes. Metabolic assessment and optimization are now considered integral components of comprehensive care, particularly in patients with obesity, diabetes, or other cardiometabolic comorbidities. Biologic therapies should be considered for patients with inadequate response to colchicine or conventional immunosuppressants, with close monitoring for adverse effects and disease progression.

Conclusion

The interplay between host metabolic states and recurrent fever syndromes is a rapidly evolving field with significant implications for diagnosis, risk stratification, and management. Advances in metabolic and immunologic research are reshaping therapeutic paradigms, offering new hope for patients with refractory or complex disease. Clinicians should maintain a high index of suspicion for metabolic contributors in recurrent fever and adopt a multidisciplinary, personalized approach to optimize outcomes. Ongoing research and collaborative efforts are essential to further elucidate pathophysiologic mechanisms and translate emerging therapies into clinical practice.