PFAPA: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome

In the Rapid Review series, I briefly review the key points of a clinical review paper. (Once again, this time it is a combination of 2 papers). The topic: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

The papers: 

Batu ED. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int. 2019;39(6):957-970. doi:10.1007/s00296-019-04257-0 PMID: 30798384

Gaggiano C, Rigante D, Sota J, Grosso S, Cantarini L. Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review. Clin Rheumatol. 2019;38(1):11-17. doi:10.1007/s10067-018-4361-2 PMID: 30488366

What is PFAPA?

PFAPA is one of the few medical conditions with a name that appropriately describes the condition, rather than being named after some old white dude. It is a disease of unknown etiology that is characterized by clock-work regular episodes of fever, aphthous stomatitis, pharyngitis, and cervical adenitis. It is primarily a disease of early childhood (less than 5 years), but an adult onset version has recently been recognized. 

How does it present?

As the name suggests, the disease presents as periodic episodes fever, aphthous stomatitis, pharyngitis, and cervical adenitis. The flares usually last around 4-5 days and recur every 3-6 weeks. The rate of occurrence does not change with the seasons, although some patients skip episodes in the summer. Patients are asymptomatic between attacks.

Fever is often high and resistant to anti-pyretics, but patients look relatively well. Erythematous or exudative pharyngitis is present in more than 90% of patients. Cervical adenitis is present in around 75% of patients. Half of patients will get oral aphthous ulcers, which are typically shallow, round ulcers less than 1 cm in size, with well demarcated erythematous margins, presenting on the non-masticatory surfaces of the mouth. Patients can also have other symptoms, such as headache, myalgias, abdominal pain, rashes, vomiting, and diarrhea.

How common is it?

It is the most common periodic fever syndrome in children, but is still pretty rare with an incidence of about 2 per 10,000.

How is it diagnosed?

It is a clinical diagnosis. Proposed diagnostic criteria are:

• Regularly recurring fevers with an early age of onset (less than 5 years) occurring in the absence of upper respiratory tract infections.
• At least one of the following:
  • Aphthous stomatitis
  • Cervical lymphadenitis
  • Pharyngitis
• Exclusion of cyclical neutropenia.
• Asymptomatic between episodes.
• Normal growth and development.

There are a few other clues, often listed alongside the diagnostic criteria:

• Abrupt cessation of symptoms after 1 or 2 doses of corticosteroids.
• A family history of recurrent pharyngitis or tonsillectomy.
• Lack of infection among family members during disease attacks.

There is also an adult onset (over 16 years old) variant, with slightly different diagnostic criteria:

• Recurrent fever accompanied by erythematous pharyngitis and/or cervical lymphadenitis.
• Increased inflammatory markers during febrile attacks.
• Presence of symptom-free intervals.

(The incidence in adults isn’t clear to me from these papers, but these diagnostic criteria make me think that we have all missed this diagnosis at least a couple times.)

What is the differential diagnosis?

Most patients with multiple visits for pharyngitis will just have recurrent infections. PFAPA should occur with more regularity, will not have other URTI symptoms such as coryza, and will not affect other family members at the same time. Cyclic neutropenia also causes recurrent fever and oral ulcers, but should be easily distinguished by the presence of neutropenia on blood work. The most difficult conditions to distinguish are the monogenic autoimmune disorders, such as familial Mediterranean fever, but from an emergency perspective I think it is enough to recognize that this is something other than recurrent infections and get a referral.

What is the cause?

We aren’t 100% sure. There is a genetic component, with familial clustering and a possible autosomal dominant pattern of inheritance. There is no known predilection for particular ethnic groups. The most likely explanation seems to be a genetically predisposed dysregulation of the immune system. The tonsils seem to be involved in pathogenesis, as the febrile episodes generally stop after tonsillectomy. 

How is it treated?

A single dose of corticosteroids – usually prednisone at 1-2 mg/kg – will rapidly resolve the PFAPA symptoms in about 90% of patients. NSAIDs are also frequently used. Although these patients are frequently given antibiotics, they are obviously ineffective. 

Once the diagnosis has been made, there are a few options to prevent recurrence. Colchicine has been used prophylactically to reduce the number of attacks, and cimetidine has also been used, but the evidence is much weaker. Tonsillectomy may be the most effective treatment option, although there does seem to be some controversy about its role, especially seeing as the disease generally resolves spontaneously after a few years.  

What is the prognosis?

The prognosis is excellent. The syndrome does not induce any long term sequelae and is not associated with comorbidities. It generally resolves spontaneously 3-5 years after symptoms onset.