What triggers adult-onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome?

Triggers for Adult-Onset PFAPA Syndrome

The most likely triggers for adult-onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome include infectious agents, stress, and genetic predisposition, though the exact etiology remains unknown.

Understanding Adult-Onset PFAPA

PFAPA syndrome is characterized by recurrent episodes of:

• High fever (typically exceeding 39°C)
• Aphthous stomatitis (mouth ulcers)
• Pharyngitis (sore throat)
• Cervical adenitis (swollen lymph nodes)

While PFAPA is primarily recognized as a childhood disorder typically affecting children under 5 years of age, adult-onset cases are increasingly being reported.

Potential Triggers

1. Infectious Agents

Various infectious agents have been implicated as potential triggers for adult-onset PFAPA, similar to what has been observed in Adult-Onset Still's Disease (AOSD), which shares some clinical features with PFAPA 1:

• Viral infections:

  • Epstein-Barr virus
  • Cytomegalovirus
  • Parvovirus B19
  • Herpes viruses
  • Influenza viruses

• Bacterial infections:

  • Mycoplasma pneumoniae
  • Chlamydia pneumoniae
  • Yersinia enterocolitica
  • Brucella abortus
  • Borrelia burgdorferi

The observation that multiple different infectious agents may act as disease triggers suggests a similarity with reactive arthritis 1.

2. Stress

Stress has been identified as an important risk factor for inflammatory conditions across all age groups 1. In adult-onset PFAPA, psychological or physiological stress may serve as a trigger for disease flares.

3. Genetic Predisposition

While no specific genetic mutation has been definitively linked to PFAPA, evidence suggests a genetic component:

• Pedigree analyses suggest an autosomal dominant pattern of inheritance 2
• The condition may represent a polygenic susceptibility pattern that requires environmental triggers 3
• PFAPA must be distinguished from other genetic periodic fever syndromes including FMF, TRAPS, HIDS, and CAPS 4

4. Immune Dysregulation

Dysregulation of the immune system appears to play a central role in PFAPA pathogenesis:

• Altered cytokine production, particularly involving:

  • IL-6
  • TNF-α
  • IL-18
  • IFN-γ

• Similar to AOSD, there may be a predominance of Th1 cytokines in the peripheral blood 1

Distinguishing Features from Other Periodic Fever Syndromes

When evaluating potential adult-onset PFAPA, it's essential to distinguish it from other periodic fever syndromes:

1. Familial Mediterranean Fever (FMF):

   • Shorter fever episodes (1-3 days)
   • Peritonitis, pleuritis
   • Erysipelas-like erythema
   • Response to colchicine
   • MEFV gene mutations

2. TNF Receptor Associated Periodic Syndrome (TRAPS):

   • Longer fever attacks (average 21 days)
   • Ocular involvement
   • Distinctive centrifugal erythematous rash
   • Strong familial distribution

3. Adult-Onset Still's Disease (AOSD):

   • Quotidian or double quotidian fever pattern
   • Evanescent salmon-pink rash
   • Arthritis/arthralgia (particularly of knees, wrists, ankles)
   • Markedly elevated ferritin levels

Diagnostic Approach

PFAPA remains a clinical diagnosis with no specific biomarkers 5, 2. Diagnosis requires:

1. Recurrent episodes of high fever with at least one of:

   • Aphthous stomatitis
   • Pharyngitis
   • Cervical adenitis

2. Symptom-free intervals between episodes

3. Exclusion of other causes:

   • Infectious diseases
   • Autoimmune disorders
   • Malignancies
   • Other periodic fever syndromes

Management Considerations

For adult-onset PFAPA, treatment options include:

1. Corticosteroids: Single-dose prednisone (1 mg/kg) during attacks provides rapid symptom resolution 2, 6

2. Colchicine: Promising for prophylaxis to decrease attack frequency 5, 2

3. IL-1 Inhibitors: May be effective but require further confirmation 3

4. Tonsillectomy: While effective in pediatric cases, evidence in adults is limited 3

Key Points for Clinicians

• Adult-onset PFAPA is increasingly recognized but remains underdiagnosed
• The exact trigger is often multifactorial, involving infectious agents, stress, and genetic predisposition
• Regular, clockwork periodicity of symptoms is a hallmark feature
• Prompt diagnosis can significantly improve quality of life 5
• Consider PFAPA in the differential diagnosis of recurrent fevers in adults when other causes have been excluded

Understanding these potential triggers can help clinicians recognize and appropriately manage adult-onset PFAPA, improving outcomes and quality of life for affected patients.