What is PFAPA Syndrome? Symptoms, Diagnosis, and Treatment

PFAPA Syndrome

PFAPA fever syndrome, one of the most common periodic fever syndromes of childhood, is an acronym for “periodic fever, aphthous stomatitis, pharyngitis, adenitis” in medical literature. It can be translated into our language as periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. First described in 1987, this disease usually begins between the ages of 2-5 and manifests itself with fever, mouth sores, symptoms of throat infection, and swelling in the neck lymph nodes.

What is PFAPA Syndrome?

PFAPA syndrome is one of the most common periodic fever syndromes encountered in childhood. It usually appears in healthy children between the ages of 2-5. Attacks recur at specific intervals, mostly in a regular pattern. Each attack lasts 3 to 6 days and can seriously affect the child's daily life, school attendance, and family life. The disease is not contagious and is often thought to be related to an overreaction of the immune system.

Although the exact cause is not known, it is estimated that some innate uncontrolled inflammatory processes in the immune system lead to this condition. PFAPA usually tends to resolve spontaneously. In some children, symptoms may persist or require treatment. Diagnosis is made by the presence of typical symptoms of the disease and the exclusion of other similar conditions. Therefore, PFAPA is a condition that requires careful observation by both the doctor and the family.

What Are the Symptoms of PFAPA Syndrome?

The most striking symptom of PFAPA syndrome is a high fever that starts suddenly and usually lasts 3 to 6 days. These fever episodes recur at specific intervals and usually appear every 3–6 weeks. One of the most common findings accompanying the fever is small, painful sores in the mouth, namely aphthae. These sores are mostly seen on the inner surface of the cheek, the edge of the tongue, or inside the lip and can make eating and speaking difficult. In addition, redness and inflammation in the throat are another common symptom. When PFAPA syndrome manifests with a sore throat, it usually does not respond to antibiotic treatment.

PFAPA syndrome is rarely seen with a cough, but it may accompany it in some children during the attack period. Painful swellings in the lymph nodes in the neck, especially in the area under the chin, become prominent enough to be felt by hand. These findings may rarely be accompanied by fatigue, loss of appetite, headache, abdominal pain, or rash. Additional symptoms are not among the basic diagnostic criteria of the disease. One of the remarkable aspects of PFAPA is that these symptoms disappear completely outside of attacks. The child appears healthy outside of fever episodes, has good energy, and their development is not affected. This cyclical course is one of the distinguishing features of the disease and facilitates the recognition of PFAPA, unlike other childhood infections.

How Does PFAPA Syndrome Occur?

This condition can be explained by the body reacting as if there were an illness despite there being no infection. In particular, the production of excessive amounts of inflammatory substances (cytokines) by certain cells involved in the immune system at specific intervals leads to the onset of attacks. It has been shown that inflammatory signals such as interleukin-1 (IL-1) in particular increase during PFAPA attacks; that is, the disease consists of periods of uncontrolled but temporary overstimulation of the immune system.

Although PFAPA is not classified as a hereditary disease, a genetic predisposition has been observed in some children. It can be seen more frequently, especially in individuals with a family history of similar fevers. It is also thought that environmental factors or small, unnoticed triggers in the body may initiate this immune response, but there is no direct relationship with any known virus or bacteria. The fact that PFAPA recurs at such regular intervals causes the disease to behave almost as if it were tied to a biological clock. This feature is one of the most distinct differences that separate it from other febrile illnesses.

How is PFAPA Syndrome Diagnosed?

PFAPA syndrome is often diagnosed not by a laboratory test, but by carefully looking at the patient's symptoms and the recurring pattern of these symptoms. The most important step in the diagnostic process is that the fever attacks the child experiences occur at regular intervals and that these attacks are accompanied by characteristic findings such as mouth sores, throat inflammation, or swelling in the neck lymph nodes. Usually, a high fever that starts suddenly while the child is in a completely healthy period lasts for a few days and then disappears completely. This cyclical picture is one of the most important clues that suggest PFAPA. Although there is no specific blood test used for PFAPA syndrome diagnostic criteria, some blood tests can be helpful. For example, inflammatory markers such as C-reactive protein (CRP) and sedimentation may increase during the attack period, but these values return to normal after the attack passes. In addition, to confirm the diagnosis, diseases showing similar symptoms must be excluded. Possibilities such as Familial Mediterranean Fever (FMF), recurrent tonsillitis, or other autoinflammatory diseases are eliminated through detailed evaluations. Another diagnostic tool is the method known as the cortisone test. If the fever drops within a few hours when a single dose of corticosteroid is given when the attack starts, it is a strong indicator supporting the diagnosis of PFAPA.

How is PFAPA Syndrome Treated?

The treatment of PFAPA syndrome is shaped according to the frequency and severity of the attacks the child experiences and their impact on daily life. A PFAPA syndrome test can be performed for infection differentials, but there is no specific test that confirms the diagnosis of the syndrome. Since each child's disease may progress differently, the treatment approach is also planned individually. One of the most common and effective methods is the administration of a single dose of corticosteroid (usually prednisolone) when an attack begins. PFAPA syndrome cortisone treatment can be applied to shorten the duration of attacks and alleviate symptoms. With PFAPA syndrome cortisone, the fever drops within a few hours in most children and symptoms disappear quickly, but in some children, this medication may cause attacks to recur more frequently. Therefore, steroid use should always be applied under the supervision of a specialist and with careful monitoring. In children who experience more frequent attacks or do not see sufficient benefit from steroid treatment, preventive (prophylactic) treatment options come into play.

In advanced cases or cases resistant to treatment, biological drugs targeting the immune system (e.g., IL-1 inhibitors) can also be used. On the other hand, in some children, tonsil and adenoid surgery (tonsillectomy + adenoidectomy) can lead to the complete cessation of attacks. Surgical treatment can be considered, especially in children who have frequent attacks and do not benefit from drug treatment, but the decision for surgery requires a detailed evaluation for each case. In addition to all these, it should not be forgotten that the disease can pass on its own over time. In many children, PFAPA either disappears completely or becomes milder and less frequent towards adolescence. The main goal in treatment is to protect the child's quality of life, prevent unnecessary antibiotic use, and provide the family with reassuring, conscious follow-up.

Frequently Asked Questions

PFAPA syndrome is a disease that mostly regresses spontaneously between the ages of 6 and 10. In many children, attacks become milder, less frequent, and eventually end completely as they approach adolescence, but this duration may not be the same for every child. While some children recover earlier, in others, it may extend beyond adolescence.

PFAPA syndrome is rarely seen in adults; in some cases, it can continue from childhood to adulthood. Those living with PFAPA syndrome usually experience attacks with similar symptoms every few weeks. The fact that PFAPA does not leave permanent damage is reassuring information for families in terms of not creating long-term anxiety. Still, how much the attacks affect the child's daily life is decisive in the management of this process. Although it is still not known exactly when and why attacks start in PFAPA, it is thought that this situation stems from the internal balance of the immune system. Although it is not a disease caused by infections, in some children, colds, seasonal changes, or small environmental changes that affect immunity can be triggers. This cannot always be explained by a consistent cause-and-effect relationship.

Its most striking aspect is that attacks appear at regular intervals, almost like a biological clock; that is, PFAPA has a rhythm of its own, and this rhythm is related to the body's internal immune responses rather than external factors. PFAPA and FMF (Familial Mediterranean Fever) are both recurrent inflammatory diseases accompanied by fever, but there are significant differences between them. PFAPA is a non-genetic syndrome that mostly starts in childhood and manifests with sore throat, aphthae, and lymph node swelling without infection.

FMF, on the other hand, is a genetic disease and often manifests with symptoms such as abdominal pain, chest pain, and joint swelling. FMF attacks can last longer than PFAPA and, if left untreated, can lead to serious complications such as amyloid accumulation in the kidneys. Furthermore, while MEFV gene mutations are investigated with genetic tests for FMF diagnosis, there is no such genetic marker for PFAPA. While FMF treatment is usually done with lifelong colchicine, PFAPA is a disease that can pass on its own and has a milder course. If a child has a fever at regular intervals and without a clear source of infection, this situation may be more than a simple chain of viral infections. In such a case, a fever diary of the child should be kept first, and the duration of each fever and accompanying symptoms (such as sore throat, mouth sores, lymph node swelling) should be noted.

Then, a pediatrician must be consulted, and if necessary, a referral to a pediatric infectious disease or rheumatology specialist should be made. Unnecessary antibiotic use provides no benefit in this case and can even be harmful. To understand the cause of the fever, similar diseases must be excluded with blood tests and a detailed physical examination. A child suspected of having PFAPA should first be evaluated by a pediatric health and diseases specialist. In cases where the diagnosis is not clear or attacks become frequent, a pediatric rheumatologist or pediatric immunology specialist must be involved. These specialists are more experienced in distinguishing recurrent fever syndromes.

If PFAPA-like complaints are encountered in adulthood, then it is necessary to consult a physician specializing in adult rheumatology. In any case, since the diagnosis and follow-up process require expertise, it is of great importance that families are directed to the correct branch. Among the diseases that cause periodic, i.e., recurring at specific intervals, fever, the most well-known is PFAPA syndrome. Apart from this, genetically transmitted autoinflammatory diseases are also in this group. For example, rare diseases such as Familial Mediterranean Fever (FMF), TRAPS (TNF receptor-associated periodic syndrome), HIDS (hyperimmunoglobulin D syndrome), and CAPS (cryopyrin-associated periodic syndrome) can also manifest with intermittent fever.

Some of these diseases can be detected with genetic tests and are hereditary. Therefore, children with constantly recurring fever attacks should be evaluated not only for infection but also for autoinflammatory diseases. Although PFAPA syndrome mostly starts in children between the ages of 2–5, it can rarely be seen in adolescence and adulthood. Adult-onset PFAPA cases are being reported more and more frequently in medical literature.

Correct Diagnosis and Safe Follow-up are Important in PFAPA Syndrome

If your child has fever attacks that recur at regular intervals, it is of great importance to correctly evaluate the underlying cause. Although PFAPA syndrome usually has a good prognosis, other diseases showing similar symptoms must be excluded.

Hisar Hospital Intercontinental Department of Pediatric Health and Diseases offers a multidisciplinary approach in the diagnosis and follow-up of recurrent fever syndromes. When necessary, a comprehensive evaluation is performed with our pediatric infectious disease and pediatric rheumatology specialists.

You can contact us for an early evaluation and correct guidance for your child's health.