OVERVIEW: What every practitioner needs to know

Are you sure your patient has PFAPA? What are the typical findings for this disease?

PFAPA (periodic fever with aphthous stomatitis, pharyngitis and adenitis) is considered one of the periodic fever syndromes (PFS), which are autoinflammatory diseases characterized by inappropriate, uncontrolled and often spontaneous inflammation in the absence of autoimmunity or infection.

PFAPA is a benign, nonhereditary, self-limited disease in young children between 2-5 yr of age charactized by episodes of sustained fever of 39°C-40.5°C lasting for 3-5 days that recur every 4-6 weeks. Between febrile episodes, patients are asymptomatic and have normal growth and development.

There is often a brief prodrome with lethargy prior to the abrupt onset of fevers, which respond poorly to antipyretics. Associated symptoms include :

1. Shallow oral ulcers (65-75% patients).

2. Non-streptococcal pharyngitis (65-75%)

3. Cervical adenopathy (75-85%).

4. Arthritis and gastrointestinal manifestations are not seen.

5. During flares: wbc 10,000-15,000/mm³ with mild neutrophila, thrombocytosis (usually <400,000/mm³) and mild to moderately increased ESR (<60).

6. Hemoglobin, urinalysis, liver function tests and serum immunoglobulins are unaffected.

7. Acute phase response resolves between fever episodes.

8. Mean duration of disease is 4.5 yr; attacks end by 10 yr of age in 90% patients; rare in adults.

9. Fevers decrease in frequency over time and eventually resolve completely.

What other conditions share some of these symptoms?

1. Cyclic neutropenia

2. Fever of unknown origin

3. HIV/AIDS

4. Tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections

5. Systemic lupus erythematosus, relapsing polychondritis

6. ANCA-mediated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis

7. Takayasu's arteritis

8. Other systemic autoinflammatory diseases*

9. HLA B27-associated juvenile spondyloarthropathies

10. Sarcoidosis

11. Malignancies, including leukemia and lymphoma

12. Autoimmune lymphoproliferative syndrome (ALPS)

13. Acute intermittent porphyria

14. Surgical emergencies, including appendicitis, intussusception

15. Relapsing pancreatitis

*Other systemic autoinflammatory syndromes that mimic PFAPA:

1. Systemic onset juvenile idiopathic arthritis, adult Still's disease

2. Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome (PAPA)

3. Chronic granulomatous synovitis with uveitis and cranial neuropathy (Blau syndrome)

4. Behcet's disease

5. Crohn's disease

6. Macrophage activation syndrome

7. Hereditary or acquired angioedema

8. Gout

9. Autoinflammatory bone diseases:

   • CRMO (chronic recurrent multifocal osteomyelitis

   • SAPHO (synovitis, acne, pustulosis, hyperostosis, osteiitis)

What caused this disease to develop at this time?

• PFAPA is an autoinflammatory, not autoimmune, disease and does not have a known trigger.

• Due to inappropriate activation and regulation of antigen-independent inflammation (innate immunity).

What laboratory studies should you request to help confirm diagnosis? How should you interpret the results?

Initial screening tests:

• CBC, differential during fever and when symptom-free

• ESR, CRP during fever and when symptom-free

• Complete metabolic panel

• Uric acid, LD

• Ferritin, fibrinoge.

• Quantitative immunoglobulins (IgG, IgA, IgM)

• Urinalysis

• Blood, urine, throat cultures

• PPD

Additional screening or diagnostic studies:

• CMV, EBV, Brucella IgM & IgG

• CMV, EBV DNA PCR

• ANA panel, ANCA.

• ACE (angiotensin converting enzyme)

• C3, C4, C1 inhibitor activity

• HLA typing (specifically for HLA B27, B51)

• IgD

Interpretation of results:

• Marked leukocytosis with left shift in association with ESR >80 and CRP >80 suggests an infectious process.

• Positive PPD suggests tuberculosis.

• Elevated uric acid or LD may suggest leukemic or other malignant process, particularly if associated with bone pain.

• Hypogammaglobulinemia suggests infection secondary to primary immunodeficiency, while hypergammaglobulinemia suggests HIV or HIDS (hyper-immunoglobulinemia D with periodic fever).

Pertinent History:

Patients with PFAPA will have documented recurrent episodes of fever >38°C for at least 4-12 months WITHOUT concurrent infectious symptoms.

The patient's history should be explored for the following characteristics:

• Peak fever temperature during the attacks

• Pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent)

• Duration of fever

• Antecedent or prodromal symptoms prior to onset of fever

• Associated symptoms (rash, arthritis, diarrhea, etc)

• Pattern of appearance of associated symptoms

• Duration of associated symptoms

• Predictability of symptoms and illness course

• Duration of fever-free intervals

• Overall health and persistent or chronic symptoms when afebrile

• Famly history of similar febrile illnesses and response to treatment

• Ethnicity of parents

• Number and type of infections in lifetime and response to antibiotics

An alternative diagnosis should be suspected if the age of onset is >5 years, there is poor growth and/or development, there are persistent symptoms or laboratory abnormalities between attacks, or additional organ involvement beyond adenopathy and oral mucosal changes are noted.

Would imaging studies be helpful? If so, which ones?

• Chest x-ray for infection, inflammatory lung disease, mass or serositis (pleuritis, pericarditis).

• Chest, abdomen, pelvis computed tomography (CT) to evaluate lymphadenopathy, mass, inflammatory lung disease, serositis.

• Bone gallium scan for osteomyelitis or tumor.

If you are able to confirm that the patient has PFAPA, what treatment should be initiated?

• Are there some therapies that should be instituted immediately?

  • None

• What about longer term treatment?

  • No treatment

  • Prednisone 1-2 mg/kg/day (max 60 mg) times 1-2 days at onset of symptoms

  • Consider cimetidine 20-40 mg/kg/day

  • Tonsillectomy (controversial as first line treatment)

• What about alternative treatments if fails standard therapy?

  • Anakinra 1 mg/kg (max 100 mg) SQ within 48 hr of attack onset; may repeat once

  • Consider colchicine 0.3-1.2 mg daily

  • Tonsillectomy

What are the adverse effects associated with each treatment option?

Table I. Adverse effects of treatment options

Table I.

Adverse effects of treatment options

What are the possible outcomes of PFAPA?

What would you tell the family about prognosis?

• Attacks end by 10 yr of age in almost all patients.

• No long term complications and normal lifespan..

• Normal growth and development.

What will you tell the family about risks/benefits of the available treatment options? (Table II)

Table II.

Risks and benefits of treatment options

What causes PFAPA and how frequent is it?

• Epidemiology:

  • No ethnic or geographic predominance.

  • 55% affected are boys.

  • Incidence unknown, but not uncommon.

  • More common than hereditary PFS or cyclic neutropenia.

• Genetics:

  • No gene defect(s) have been identified.

How do pathogens/genes/exposure cause the disease?

No known genetic predisposition or defined triggers for flares.

Other clinical manifestations that might help with diagnosis and management

None

What complications might you expect from the disease or treatment of the disease?

1. Complications are mild, brief and self-limited.

2. Treatment complications may be more common than from disease.

Are additional laboratory studies available; even some that are not widely available?

Consider genotyping for known inherited periodic fever syndromes to exclude these diagnoses.

How can PFAPA be prevented?

No known prevention.

What is the evidence?

Marshall, GS, Edwards, KM, Butler, J, Lawton, AR. "Syndrome of periodic fever, pharyngitis, and aphthous stomatitis". J Pediatr. vol. 110. 1987. pp. 43.

Thomas, KT, Feder, HM, Lawton, AR, Edwards, KM. "Periodic fever syndrome in children". J Pediatr. vol. 135. 1999. pp. 15.

Caorsi, R, Pelagatti, MA, Federici, S, Finetti, M, Martini, A, Gattorno, M. "Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome". Curr Opin Rheumatol. vol. 22. 2010. pp. 579.

Burton, MJ, Polard, AJ, Ramsden, JD. "Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)". Cochrance Database Syst Rev. 2010: Sep 8.

Gattorno, M, Caorsi, R, Meini, A, Cattalini, M, Federici, S, Zulian, F. "Differentiating PFAPA syndrome from monogenic periodic fevers". Pediatrics. vol. 124. 2009. pp. e721.

Caorsi, R, Pelagatti, MA, Federici, S, Finetti, M, Martini, A, Gattorno, M. "Periodic fever, apthous stomatitis, pharyngitis and adenitis syndrome". Curr Opin Rheumatol. vol. 22. 2010. pp. 579.

Stojanov, S, Lapidus, S, Chitkara, P, Feder, H, Salazar, JC, Fleisher, TA. "Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade". Proc Natl Acad Sci. April 8, 2011.

Ongoing controversies regarding etiology, diagnosis, treatment

1. Best management of PFAPA: steroids versus tonsillectomy versus IL-1 blockade versus no treatment.