PFAPA Symptoms and Treatment

OVERVIEW: What every practitioner needs to know

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

PFAPA symptoms (periodic fever with aphthous stomatitis, pharyngitis and adenitis) are 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 :

• Shallow oral ulcers (65-75% patients).
• Non-streptococcal pharyngitis (65-75%)
• Cervical adenopathy (75-85%).
• Arthritis and gastrointestinal manifestations are not seen.
• During flares: wbc 10,000-15,000/mm³ with mild neutrophila, thrombocytosis (usually <400,000/mm³) and mild to moderately increased ESR (<60).
• Hemoglobin, urinalysis, liver function tests and serum immunoglobulins are unaffected.
• Acute phase response resolves between fever episodes.
• Mean duration of disease is 4.5 yr; attacks end by 10 yr of age in 90% patients; rare in adults.
• Fevers decrease in frequency over time and eventually resolve completely.

What other conditions share some of these PFAPA symptoms?

• Cyclic neutropenia
• Fever of unknown origin
• HIV/AIDS
• Tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections
• Systemic lupus erythematosus, relapsing polychondritis
• ANCA-mediated vasculitis, including Wegener’s granulomatosis and microscopic polyangiitis
• Takayasu’s arteritis
• Other systemic autoinflammatory diseases*
• HLA B27-associated juvenile spondyloarthropathies
• Sarcoidosis
• Malignancies, including leukemia and lymphoma
• Autoimmune lymphoproliferative syndrome (ALPS)
• Acute intermittent porphyria
• Surgical emergencies, including appendicitis, intussusception
• Relapsing pancreatitis

*Other systemic autoinflammatory syndromes that mimic PFAPA:

Systemic onset juvenile idiopathic arthritis, adult Still’s disease

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

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

Behcet’s disease

Crohn’s disease

Macrophage activation syndrome

Hereditary or acquired angioedema

Gout

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 for PFAPA symptoms:

• 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 symptoms, 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 for PFAPA symptoms?

Table I. Adverse effects of treatment options

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