PFAPA Syndrome

What is PFAPA syndrome?

PFAPA syndrome is a childhood condition that causes fevers that come back again and again in a strikingly regular pattern. The name is an abbreviation of its main features: Periodic Fever, Aphthous stomatitis (small, painful mouth ulcers), Pharyngitis (a sore, inflamed throat) and cervical Adenitis (swollen, tender lymph nodes in the neck). It is sometimes called Marshall syndrome, after the doctor who first described it.

PFAPA syndrome belongs to a group of conditions known as autoinflammatory diseases. In these conditions, the body’s innate immune system, the first line of defense against infection, switches on without an infection or other clear trigger being present. The fever episodes in PFAPA syndrome are therefore not caused by a virus or bacteria, and they are not contagious.

The condition most often begins in early childhood, typically before the age of five, and it appears to affect boys slightly more often than girls. In most children the episodes gradually become less frequent and eventually stop on their own, usually before or around the teenage years. PFAPA syndrome has also been described in older children and, less commonly, in adults, although this is much rarer. Because it is a pediatric condition in the great majority of cases, it is usually evaluated and managed by a pediatrician, often working with a pediatric rheumatologist (a doctor who specializes in inflammatory and immune conditions) or an ear, nose and throat specialist.

PFAPA syndrome symptoms

The hallmark of PFAPA syndrome is the predictability of the episodes. Many parents notice that the fevers arrive almost like clockwork, and some can even mark the next expected episode on a calendar. A typical episode includes:

• A sudden high fever, often above 39°C (102°F), that lasts about three to six days
• A sore throat with redness of the tonsils, sometimes with white patches, that looks like tonsillitis
• Small, shallow mouth ulcers (aphthous ulcers) on the inside of the lips or cheeks
• Swollen, tender lymph nodes on the sides of the neck
• Tiredness, irritability and reduced appetite during the episode
• Sometimes headache, abdominal pain, nausea or mild joint aches
• Occasionally chills at the start of the fever

Not every child has all four of the classic features during every episode. A sore throat is the most common feature, while mouth ulcers are seen less consistently and may be small enough to be missed. Between episodes the child is completely well, grows normally and develops normally. This healthy period between flares is one of the most important clues that separates PFAPA syndrome from other causes of recurring fever.

The interval between episodes is usually somewhere between three and eight weeks and tends to be fairly constant for an individual child, although it can vary from one child to another. Over time, as the child gets older, episodes often become milder, shorter and further apart before stopping altogether. Symptoms such as a runny nose, cough, wheezing or a widespread rash are not typical of PFAPA syndrome and usually point to a common infection instead.

PFAPA syndrome causes and risk factors

The exact cause of PFAPA syndrome is not fully understood. Researchers believe it results from a temporary dysregulation of the innate immune system, in which inflammatory chemical messengers (cytokines) are released in bursts, producing fever and inflammation of the throat, mouth and neck lymph nodes. Why this happens in a cyclical pattern is still being studied.

Unlike many other periodic fever syndromes, PFAPA syndrome is not caused by a single identified gene mutation, and it is not considered a classic inherited disorder. That said, some studies have found that other family members occasionally report a history of similar recurrent fevers or of having their tonsils removed in childhood, so a genetic tendency may play a part in some families. PFAPA syndrome is not caused by infection, is not passed from child to child, and is not the result of anything a parent did or did not do.

Factors that appear to be associated with PFAPA syndrome include:

• Young age: onset is most common between about one and five years of age
• Male sex: boys are affected somewhat more often than girls
• Family history: a relative with recurrent childhood fevers or early tonsillectomy is reported in some cases

Environmental factors, diet, allergies and stress have not been shown to cause PFAPA syndrome, although some parents feel that episodes are occasionally triggered by tiredness or a minor illness. There is currently no known way to prevent the condition from developing.

PFAPA syndrome diagnosis

There is no single blood test, scan or genetic test that confirms PFAPA syndrome. It is a clinical diagnosis, meaning the doctor makes it by carefully piecing together the pattern of symptoms and by ruling out other explanations. The process usually involves several steps.

Detailed history. The doctor will ask about the timing, length and regularity of the fevers, the symptoms that accompany them, how the child is between episodes, and whether antibiotics have ever seemed to help (in PFAPA syndrome they generally do not). Keeping a fever diary that records dates, temperatures and symptoms is often very helpful at this stage.

Physical examination. Ideally the child is examined during an episode, when the doctor can see the red tonsils, mouth ulcers and swollen neck glands, and again when well, to confirm that everything has returned to normal.

Blood tests. During a flare, inflammatory markers such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are usually raised, and the white blood cell count may be elevated. Between episodes these results typically return to normal. Blood tests are also used to check for other conditions, for example cyclic neutropenia, a disorder in which a type of infection-fighting white blood cell periodically drops to very low levels.

Throat swab. A rapid strep test or throat culture is often taken during an episode to check for streptococcal bacteria. In PFAPA syndrome the result is expected to be negative.

Genetic testing. If the picture is not typical, if episodes are unusually long, or if there are features such as rash, severe abdominal pain, chest pain or a family origin associated with other periodic fever syndromes, the doctor may order genetic tests to look for inherited conditions such as familial Mediterranean fever, TRAPS or mevalonate kinase deficiency.

Doctors commonly use published clinical criteria that include regularly recurring fevers starting in early childhood, at least one of the three accompanying features (mouth ulcers, sore throat or neck lymph node swelling), complete well-being between episodes with normal growth, and the exclusion of cyclic neutropenia and other causes. In some cases the response to a single dose of a corticosteroid, described below, is used as supporting evidence. Imaging is not usually needed for PFAPA syndrome itself.

PFAPA syndrome treatment options

Because PFAPA syndrome is not dangerous in itself and tends to resolve with time, treatment is aimed at relieving symptoms, shortening episodes and, in selected children, reducing how often they occur. The right approach depends on how severe the episodes are and how much they disrupt the child’s and family’s life. Options are usually discussed with a pediatrician; at Acibadem this condition is managed within the Pediatrics department.

Observation and supportive care. For mild episodes, many families choose simply to manage symptoms at home. This includes rest, plenty of fluids, soft foods and cool drinks to ease throat and mouth pain, and standard doses of acetaminophen (paracetamol) or ibuprofen for fever and discomfort. These medicines can make the child more comfortable, but they do not usually stop the episode. Antibiotics do not help, because there is no bacterial infection.

Corticosteroids. A single dose of an oral corticosteroid such as prednisolone, given at the very start of an episode, often brings the fever down dramatically within a few hours and is one of the most characteristic responses in PFAPA syndrome. The dose is prescribed by the doctor based on the child’s weight. A possible drawback is that in some children the interval between episodes becomes shorter after steroid use. Because each episode requires only a single dose, long-term steroid side effects are not usually a concern, but the frequency of use should be reviewed by the doctor.

Preventive medication. For children with very frequent or disruptive episodes, the doctor may consider a daily preventive medicine. Colchicine, a long-established anti-inflammatory drug, has been reported to lengthen the interval between episodes in some children. Cimetidine, an older acid-reducing medicine with mild immune-modifying effects, has been used for the same purpose with variable results. These medicines do not work for everyone, and their use is decided case by case.

Tonsillectomy. Surgical removal of the tonsils, sometimes together with the adenoids, has been shown in many children to end the episodes or make them much less frequent. Exactly why this works is not fully understood, but the tonsils appear to be an important site of the abnormal inflammatory response. Surgery is generally reserved for children whose episodes are severe, frequent or poorly controlled by medicines, or for families who prefer a definitive option. Like any operation, tonsillectomy carries risks, including bleeding and pain during recovery, and it is not a guaranteed cure. The decision is made together with an ear, nose and throat surgeon after weighing benefits and risks, remembering that the condition usually resolves on its own eventually.

Newer approaches. Medicines that block specific inflammatory messengers, known as biologic agents, have been studied in small numbers of children with difficult cases, but they are not part of routine care for PFAPA syndrome.

Living with PFAPA syndrome and outlook

The long-term outlook for children with PFAPA syndrome is generally reassuring. The condition does not cause lasting damage to organs, does not affect growth or development, and is not linked to later serious illness. In most children the episodes gradually fade and stop, often within several years of starting and usually by adolescence. A small number of people continue to have occasional episodes into adulthood, and rare cases first appear in adults, but even then the episodes are usually manageable.

The main burden of PFAPA syndrome is practical and emotional. Regular fevers mean missed days of nursery or school, missed work for parents, interrupted sleep and understandable worry each time a fever appears. Several strategies can help:

• Keeping a fever diary to track the pattern and support treatment decisions
• Having a written plan from the doctor about what to do at the start of an episode
• Informing the school or nursery that the fevers are not contagious and that the child recovers fully
• Planning holidays and important events around the expected cycle when possible
• Continuing routine childhood vaccinations, which are safe and recommended

Regular follow-up allows the doctor to check that the pattern remains typical, to review how well treatment is working, and to reconsider the diagnosis if new or unusual symptoms appear.

Frequently asked questions

Is PFAPA syndrome contagious?

No. PFAPA syndrome is an autoinflammatory condition, meaning the fever comes from the body’s own immune system rather than from an infection. Children with PFAPA syndrome cannot pass it to siblings, classmates or adults, and they do not need to be isolated during an episode, although many feel too unwell to attend school while the fever lasts.

What are the most common PFAPA syndrome symptoms?

The most common PFAPA syndrome symptoms are a sudden high fever lasting several days, a sore throat with red tonsils, painful mouth ulcers and swollen neck glands, returning at regular intervals of a few weeks. Between episodes the child is well. Coughs, runny noses and widespread rashes are not typical and usually suggest an ordinary infection instead.

What causes PFAPA syndrome and can it be inherited?

The precise PFAPA syndrome causes are not known. It is thought to involve a temporary misfiring of the innate immune system that releases inflammatory chemicals in a cyclical way. No single gene has been identified, so it is not considered a classic inherited disease, although a family history of similar fevers is reported in some cases, suggesting that genetics may contribute in certain families.

How is a PFAPA syndrome diagnosis made?

PFAPA syndrome diagnosis is based on the clinical pattern rather than on one specific test. Doctors look for regular fevers starting in early childhood, at least one of the accompanying throat, mouth or neck-gland features, complete health between episodes and normal growth. Blood tests, throat swabs and sometimes genetic tests are used to rule out infections, cyclic neutropenia and other periodic fever syndromes.

What is the best PFAPA syndrome treatment?

There is no single best PFAPA syndrome treatment; the choice depends on how much the episodes affect the child. Options range from simple fever relief at home, to a single dose of a corticosteroid at the start of each episode, to daily preventive medicines such as colchicine, to tonsillectomy for frequent or severe cases. Your child’s doctor can help weigh these options.

Do antibiotics help PFAPA syndrome?

Antibiotics do not help PFAPA syndrome because the fever and sore throat are not caused by bacteria. Many children receive several courses of antibiotics before the diagnosis is made, since each episode can look like tonsillitis. Once PFAPA syndrome is recognized, avoiding unnecessary antibiotics protects the child from side effects and helps limit antibiotic resistance.

Will my child outgrow PFAPA syndrome?

In most cases, yes. Episodes tend to become milder and less frequent as the child grows, and they usually stop on their own within several years, often before adolescence. The condition does not cause long-term harm. A small number of people continue to have occasional episodes into adulthood, but this is uncommon and no outcome can be promised for an individual child.

When to see a doctor

Any child with fevers that keep returning in a regular pattern should be assessed by a doctor so that the cause can be identified and other conditions ruled out. If your child already has a diagnosis of PFAPA syndrome, routine follow-up is still important, and you should arrange a review if the pattern of episodes changes, if a new symptom appears, or if treatment no longer seems to work.

Seek urgent medical attention if your child has any of the following, whether or not PFAPA syndrome has been diagnosed:

• Fever in a baby younger than three months
• A fever that lasts longer than the child’s usual episode or does not settle as expected
• Difficulty breathing, noisy breathing or drooling with an inability to swallow
• A stiff neck, severe headache, sensitivity to light or unusual drowsiness
• A rash that does not fade when pressed, or purple spots on the skin
• Signs of dehydration such as very little urine, dry mouth, no tears or sunken eyes
• A seizure (fit) or the child being difficult to wake
• Severe abdominal pain, chest pain, joint swelling or repeated vomiting
• Any time you feel your child looks seriously unwell or is getting worse quickly

These signs can indicate a serious infection or another condition that needs immediate treatment, and they should never be assumed to be part of PFAPA syndrome.