Recurring or unexplained fevers, also termed recurrent or relapsing fever of unknown origin (FUO) often prompt suspicion of an undetected infection.
However, not all cyclical fevers stem from microbial pathogens.
A growing subset of febrile conditions originate from non-infectious immunologic dysregulation, auto-inflammatory mechanisms, or malignancy-associated cytokine activity. This emerging perspective is shifting diagnostic algorithms in internal medicine.
According to a recent study, only 25% of prolonged fevers with a relapsing pattern are ultimately linked to infectious sources. The rest often involve systemic inflammatory responses without microbial involvement.
Cytokine Storms and Thermoregulatory Dysfunction
The human hypothalamic set-point is tightly regulated by cytokine signaling, primarily via interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These molecules are elevated during infections but may also be persistently activated in autoimmune diseases, hematologic malignancies, or periodic fever syndromes.
Dr. Charles A. Dinarello, a physician-scientist renowned for his work on cytokines and fever mechanisms, states, "Endogenous cytokines such as IL‑1, IL‑6, and TNF‑α elevate the hypothalamic set‑point, leading to fever—even in non-infectious inflammatory states like autoimmune or autoinflammatory disorders."
This phenomenon is particularly seen in familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and adult-onset Still's disease (AOSD).
Auto-Inflammatory Syndromes: Cycles Without Contamination
Autoinflammatory conditions, distinct from autoimmune diseases, involve innate immune hyperactivity without detectable antibodies or antigens. In these cases, the periodic fever is a core diagnostic marker. These syndromes often present in early life but may remain under-recognized in adult populations.
Examples include:
- Mevalonate kinase deficiency (MKD)
- Cryopyrin-associated periodic syndromes (CAPS)
- AOSD, where ferritin levels are disproportionately elevated during febrile phases
Such disorders are increasingly diagnosed using next-generation genetic sequencing, which can reveal mutations in inflammasome-related pathways, such as NLRP3.
Hematologic Triggers: Fever as a Malignant Signal
In some patients, especially older adults, recurring fevers may point toward paraneoplastic syndromes or early-stage hematologic neoplasms, such as lymphomas or myeloproliferative disorders. Fever in these cases arises from abnormal cytokine release by dysplastic immune cells or the tumor microenvironment.
A recent study identified fever as the initial symptom in over 10% of chronic lymphocytic leukemia (CLL) diagnoses, even before lymphocyte abnormalities were clinically evident.
Clinical red flags include:
- Fever resistant to antimicrobials
- No clinical signs of infection despite elevated C-reactive protein (CRP)
- Accompanying systemic symptoms like night sweats or unexplained weight changes
Drug-Induced Fever: The Invisible Side Effect
Drug fever remains a frequently missed diagnosis. Certain pharmaceuticals including anticonvulsants, antibiotics (e.g., beta-lactams), and biologics can induce immune-mediated pyrexia without accompanying inflammation or infection. This is typically a diagnosis of exclusion and becomes more likely if fever arises 5–10 days after starting a new medication and resolves promptly after discontinuation.
Laboratory features such as eosinophilia or atypical lymphocytosis may occasionally accompany the febrile response.
Endocrine and Metabolic Factors in Fever
Although less common, dysregulated hormonal signaling and metabolic disorders can contribute to thermoregulatory instability. For example, pheochromocytoma—a rare catecholamine-producing tumor can cause paroxysmal fevers due to episodic adrenaline surges. Similarly, thyroid hormone dysregulation, particularly in the form of subclinical thyrotoxicosis, has been implicated in low-grade but persistent temperature elevations.
In such cases, advanced imaging, including functional MRI or nuclear medicine scans, may be necessary to reveal the underlying etiology.
Advanced Diagnostic Strategy: When Conventional Labs Fall Short
A tiered diagnostic approach is now recommended when investigating recurrent unexplained fever:
Initial Panel: CBC, CRP, ESR, procalcitonin, blood cultures (including extended incubation sets)
Second-Line Tests: ANA, rheumatoid factor, serum ferritin, SPEP/UPEP, LDH
Targeted Genetic Testing: For periodic fever syndromes or hereditary auto-inflammatory disorders
Imaging: PET-CT or whole-body MRI in suspected neoplastic or granulomatous conditions
Bones marrow biopsy: If hematologic abnormalities or persistent cytopenias are noted
The timing and pattern of the fever are often diagnostic clues. For example, quotidian fevers (spiking at the same time daily) are suggestive of Still's disease, while fever cycles lasting 21 days may hint at cyclic neutropenia.
Treatment Principles: Individualization Is Critical
Therapeutic strategies must target the underlying mechanism rather than the fever itself. Inappropriate or prolonged use of antimicrobials can delay accurate diagnosis and contribute to resistance. Examples of effective interventions include:
- IL-1 inhibitors (e.g., anakinra) for AOSD or CAPS
- Corticosteroids for immune-mediated fever
- Anti-TNF agents in TRAPS and related conditions
Fever without infection is more than a diagnostic curiosity—it's a clinical puzzle that demands a broad differential, immunologic insight, and sometimes genetic exploration. Misattributing these fevers to recurrent infections can lead to mismanagement and delayed intervention in serious systemic conditions.
As research deepens, physicians are urged to treat the cause, not the temperature—a principle that will continue to guide accurate, evidence-based care in the era of personalized medicine.
