Periodic Fever, Aphthous Stomatitis, Pharyngitis, & Cervical Adenitis Syndrome (PFAPA Syndrome) Research and Information

Below are links to helpful research and information about periodic fever, aphthous stomatitis, pharyngitis, & cervical adenitis syndrome (PFAPA syndrome). These are not all the studies available however. For more search Pubmed.gov.

Eurofever Classification Criteria – This diagnostic questionnaire by the EUROFEVER project is really helpful for doctors considering symptoms when trying to diagnose some of the hereditary periodic fever (autoinflammatory) syndromes, like CAPS, TRAPS, HIDS and FMF. CAPS, TRAPS, HIDS, and FMF all have symptoms similar to PFAPA.

Autoinflammatory Diseases Online Database – This compares the most notable and classic symptoms and lab results for the known periodic fever syndromes including PFAPA.

UpToDate – Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome) – This gives details on the diagnostic criteria, differential diagnosis, and treatments for PFAPA. Notes are also made on what would exclude the diagnosis of PFAPA; these include symptoms between flares, abnormal labs, such as elevated CRP, between flares, and neutropenia. The authors note that, “The following symptoms as a part of most attacks should trigger consideration of other diagnoses: cough, coryza, severe abdominal pain, significant diarrhea, rash, arthritis, or neuromuscular symptoms.”

Diagnostic criteria of PFAPA per UpToDate:

  • At least 3 episodes of fevers lasting no more than 5 days that occur at regular intervals. It’s noted that, “For individual patients, intervals between attacks are nearly identical within a range of three to six weeks, and the symptoms with each episode are identical.”
  • Pharyngitis with swollen cervical lymph nodes and/or with mouth ulcers.
  • Normal growth and no symptoms between flares.
  • Resolution of symptoms with a single dose of prednisone. (Do note that PFAPA is not the only fever syndrome that responds to prednisone.)

Further per UpToDate: “Clinical features that exclude PFAPA include: the presence of neutropenia before or during an episode, the presence of atypical symptoms (ie, cough, coryza, severe abdominal pain, diarrhea, rash, arthritis, or neurologic deficits) in association with most episodes, an elevated ESR or CRP between attacks, impaired growth, or a family history of recurrent fever.

To Make the PFAPA Syndrome More Familiar Questions & Answers by Dr. Beata Wolska-Kusnierz, MD-PhD – This PDF gives a good detailed overview of PFAPA. Some highlights:

  • Between the recurrent episodes, children don’t complain about any ailments and do not manifest any worrying symptoms during the medical examination.
  • The lack of remission after tonsillectomy will indicate the direction of extended diagnostics, e.g. toward genetic autoinflammatory illnesses.
  • There are absolutely no contraindications against immunization. Vaccines have no impact on PFAPA.
  • Vitamin D3 supplements should be given…(Read PDF for dosage information.)
  • Usually no skin changes are observed with patients suffering from PFAPA…If urticaria or other skin changes occur together with the recurrent high fever episodes, autoinflammatory illnesses other than PFAPA should be considered in the diagnostic process. (Click here for the comparison chart of periodic fever syndromes.)
  • Diet does not affect the course of PFAPA.

Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome Is Associated with a CARD8 Variant Unable To Bind the NLRP3 Inflammasome.  – “As a result, the mutant CARD8 protein lost the ability to interact with the NOD domain of NLRP3. In summary, these results identify a new CARD8 variant associated with PFAPA and further suggest that disruption of the interaction between CARD8 and NLRP3 can regulate autoinflammation in patients.”

A 2-Year-Old Patient Has Had Recurrent Fevers For The Last Year. He Often Has A Red Throat, Adenopathy, And Stomatitis With His Fevers. I Am Concerned About Periodic Fever, Aphthous Stomatitis, Pharyngitis And Cervical Adenitis Syndrome. What Are The Treatment Options For This Diagnosis? – A discussion of diagnosing PFAPA. From this article, “The various periodic fever syndromes have overlapping symptoms; therefore, a definitive diagnosis of PFAPA cannot be made until other periodic fever syndromes have been excluded via genetic testing…” It also covers treatment options.

PFAPA Syndrome – A simple definition of PFAPA – of interest is this statement: “Neutropenia or other symptoms (eg, diarrhea, rash, cough) are not present; their presence suggests a different disorder.” Statement reviewed by Dr. Stephen E. Goldfinger.

Colchicine trial in PFAPA Syndrome and MEFV-negative patients – 27 of 36 PFAPA patients had a good response to colchicine in that flare frequency and/or severity of flares were reduced. Dosing was similar to what is used for FMF patients.

The Pathogenesis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome: A Review of Current Research – A 2015 review of what is known about what causes PFAPA. “Recent findings suggest that there is a familial tendency to PFAPA but the level of evidence does not warrant definite conclusions. The absence of a clear monogenic trait indicates a heterogenous, polygenic, or complex inheritance of PFAPA syndrome. As two mutations with a possible functional effect on the inflammasomes (MEFV E148Q and NLRP3 Q703K) have been found in several PFAPA cohorts, the role of inflammasome-related genes in PFAPA pathogenesis cannot be excluded. Immunological mechanisms of PFAPA involve an abnormal, IL-1β dependent innate immune response to an environmental trigger, which leads to Th1-driven inflammation expressed by recruitment of T-cells to the periphery.”

Physicians employ flexible diagnostic criteria for PFAPA in children – Rheumatologists were surveyed on their adherence to the PFAPA diagnostic criteria when diagnosing PFAPA. It was found that a high percentage of physicians were not applying all aspects of the diagnostic criteria. According to the study authors, “We found that physicians did not adhere to their original criteria, and that physicians almost used it as a field test: if it seems like PFAPA, then they diagnose it as PFAPA.”

Could MEFV gene mutations be related to PFAPA syndrome? – “We evaluated 64 patients with PFAPA syndrome…An MEFV gene mutation was found in 42 (66.0%) children.”

Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthoous stomatitis, pharyngitis, and vervical adenitis (PFAPA) syndrome – “vitamin D supplementation seems to significantly reduce the typical PFAPA episodes and their duration, supporting the role of vitamin D as an immune-regulatory factor in this syndrome.”

Follow-up of Children with PFAPA Syndrome – 50 of 59 PFAPA patients had resolution of fever flares an average of 6.3 years after symptoms started. Three patients received another diagnosis including Behcet’s and FMF. Authors note, “Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out.”

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. Our data strongly suggest that IL-1β monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants, suggesting that inflammasome-related genes might be involved in this autoinflammatory syndrome.

Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf

SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

The mean platelet volume levels in children with PFAPA syndrome. The mean platelet volume for PFAPA patients was found to be lower, both during fever flares and between flares, than health controls. In the PFAPA patients, the platelet values were lower during flares than between flares.

PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort.

Differentiating PFAPA Syndrome From Monogenic Periodic Fevers From this study: “patients with monogenic periodic fevers also meet the diagnostic criteria for PFAPA syndrome… 83% of patients with MKD, 57% of patients with TRAPS, and 8% of patients with FMF satisfied the criteria for PFAPA syndrome…We found that some of the features that are considered characteristic of PFAPA syndrome, such as clockwork-like recurrence of febrile episodes, oral aphthosis, and enlargement of cervical lymph nodes, are present with similar frequencies in MKD and also may be present in some genetically proven pediatric FMF cases.”

PFAPA vs. HIDS – Without genetic testing it can be very difficult in some patients to differentiate between HIDS and PFAPA. This comprehensive chart compares the typical presentation of PFAPA to the typical presentation of HIDS.

Tonsillectomy efficacy is comparable to the standard medical treatment in PFAPA syndrome

NIH researchers identify cause and new treatment for common recurrent fever in childrenKineret is a viable treatment for PFAPA – “The anakinra treatment has the potential to restore these children to a mostly symptom-free childhood,” said Dr. Kastner.”

PFAPA syndrome is not a sporadic disease-Report about the number of patients with a positive family history for periodic fever symptoms.

Urban Legends Series: Recurrent Aphthous Stomatitis – This discusses the difficulty of differentiating HIDS, TRAPS, and FMF from PFAPA without genetic testing due to overlapping symptoms. “In this case-control study of 210 children that met the clinical criteria for PFAPA syndrome, 38% were genetically positive for either MKD, FMF, TRAPS or displayed low penetrance or incomplete mutations, and 62% had negative genetic testing profiles (Gattorno et al., 2009)…. Cardinal features of the PFAPA syndrome, such as oral aphthosis and enlargement of cervical lymph nodes, were observed with similar frequencies in genetically negative patients and in subjects positive for MKD and FMF.”

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to Il-1 blockade – a comprehensive study of the PFAPA biological process by the NIH. Discusses possible biomarkers that can be used as a test to help confirm PFAPA.

Tonsillectomy in children with periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome

A clinical review of 105 patients with PFAPA (a periodic fever syndrome) – This is the diagnostic criteria used: “Subjects met our case definition of PFAPA (i) if they had at least six episodes of documented fever (T>38.9C), (ii) if each febrile episode lasted no more than 10 days, (iii) if the fevers recurred at regular intervals of 2–8 weeks, (iv) if they were well between febrile episodes, (v) if they did not have arthritis or a distinctive rash or documented neutropenia and (vi) if they did not have a clinical explanation for the fever other than PFAPA. In addition to fever, patients needed to have at least one of the three major clinical findings associated with PFAPA – aphthous stomatitis, pharyngitis or cervical adenitis.”

PFAPA: a single phenotype with genetic heterogeneity – evidence that PFAPA may be  genetic.

Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA).

PFAPA syndrome in children: A meta-analysis on surgical versus medical treatment

Vitamin D linked to PFAPA syndrome.

Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. – This is a follow up of 102 PFAPA patients who underwent adenotonsillectomy. “99 had complete resolution of symptoms immediately after surgery,” report the study authors. One child who did not respond to surgery was later found to have HIDS.

 

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