A fever is the body’s common, temporary response to an infection, signaling that the immune system is actively fighting an invading pathogen. A fever syndrome, however, represents a group of conditions where the fever is not caused by an external source like a virus or bacterium. These disorders, known as Periodic Fever Syndromes (PFS), are characterized by recurring, intense episodes of fever and inflammation without an obvious infectious trigger. Their cause lies in a malfunction of the body’s internal defense system, making them complex and chronic medical conditions.
Defining Periodic Fever Syndromes
Periodic Fever Syndromes (PFS) are defined by a hallmark pattern of inflammation that is both recurrent and predictable. Individuals experience episodes of high fever and systemic symptoms lasting a defined period, followed by complete remission where they are entirely symptom-free. This cyclical pattern differentiates PFS from persistent or chronic fevers.
The episodes are separated by symptom-free intervals ranging from a few weeks to several months. During a flare, the body exhibits clear signs of inflammation, such as elevated white blood cell counts and high levels of C-reactive protein (CRP). These inflammatory episodes are sterile, occurring without any detectable external pathogen. This intrinsic nature means antibiotics are ineffective, pointing toward an issue in the body’s self-regulatory mechanisms.
The Underlying Mechanisms of Autoinflammation
The root cause of Periodic Fever Syndromes is autoinflammation, which originates in the innate immune system. The innate system is the body’s first line of defense, designed to react immediately to danger signals from pathogens or damaged cells. In autoinflammatory disorders, components of this system become hyperactive or unable to properly switch off.
This malfunction often stems from a genetic change that affects proteins controlling inflammation. For example, in many hereditary syndromes, the defect involves the inflammasome, a multi-protein complex within immune cells. Incorrect activation of the inflammasome drives the overproduction of powerful pro-inflammatory signaling molecules, primarily Interleukin-1 beta (IL-1 \(\beta\)).
The resulting inflammation is sterile because it is not a response to an infection. Instead, the innate immune system mistakenly perceives an internal threat, triggering a systemic inflammatory cascade that manifests as fever and joint pain. These genetic defects cause the body to spontaneously erupt in inflammatory episodes. PFS are distinct from autoimmune diseases, which primarily involve the adaptive immune system attacking the body’s own tissues.
Common Categories of Fever Syndromes
The term Periodic Fever Syndrome encompasses several specific conditions, each with its own defining set of symptoms and genetic origins.
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA)
PFAPA is the most frequently identified periodic fever syndrome, typically starting in children between the ages of two and five. The name is an acronym for its four primary symptoms: recurrent high Fever, painful Aphthous stomatitis (mouth ulcers), Pharyngitis (sore throat), and Adenitis (swollen lymph nodes in the neck). Episodes of high fever usually last three to six days and recur regularly, often every three to eight weeks. Between flares, the child is completely healthy and shows normal growth and development.
Familial Mediterranean Fever (FMF)
FMF is a genetic autoinflammatory disorder caused by mutations in the MEFV gene, which codes for the pyrin protein. This condition is most prevalent in populations of Mediterranean and Middle Eastern descent. FMF attacks are short-lived, lasting between one and three days, and are characterized by fever accompanied by severe inflammation in the abdomen, chest, or joints. Recurrent inflammation of the abdominal lining (peritonitis) can sometimes be severe enough to be mistaken for appendicitis.
TNF Receptor-Associated Periodic Syndrome (TRAPS)
TRAPS is caused by a mutation in the TNFRSF1A gene, which affects a receptor for the tumor necrosis factor (TNF) protein. Unlike FMF, TRAPS episodes tend to be prolonged, often lasting from seven to twenty-one days. Distinctive features include migratory myalgia (muscle pain that moves across the limbs) and a painful, non-itchy rash. Eye inflammation, such as conjunctivitis or periorbital edema (swelling around the eyes), is a common symptom.
Diagnosis and Treatment Approaches
Diagnosing a periodic fever syndrome begins with a detailed medical history and the careful tracking of symptoms to establish the characteristic recurrent pattern. Since symptoms can mimic common infections, diagnosis involves excluding other possibilities, such as infectious diseases, malignancies, and autoimmune conditions. During an inflammatory episode, blood tests show a marked elevation in inflammatory markers, which return to normal in the symptom-free period.
Genetic testing is frequently used to confirm the diagnosis for inherited forms, specifically looking for mutations in genes like MEFV or TNFRSF1A. For conditions where a genetic link is not fully established, such as PFAPA, diagnosis relies on meeting specific clinical criteria and ruling out other causes.
Treatment strategies focus on controlling inflammation to prevent organ damage and reduce the frequency and severity of attacks. For FMF, the drug colchicine is the standard treatment, preventing attacks and protecting against the long-term complication of amyloidosis. For other syndromes, treatments may include non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids to manage acute flares. More targeted biological therapies, such as those that block pro-inflammatory cytokines like Interleukin-1 (IL-1), are highly effective at controlling the chronic, unregulated immune response.