ESPID Reports and Reviews
The “periodic fever, aphthous stomatitis, pharyngitis and adenitis” (PFAPA) syndrome is a clinical entity that was first recognized by Marshall in 1987 and is characterized by (1) an onset before the age of 5 years; (2) quite regularly recurring episodes of fever, with at least 1 of the 3 associated constitutional signs of aphthous stomatitis, pharyngitis or cervical adenitis without any signs of upper respiratory tract infection; (3) completely asymptomatic interfebrile periods with normal growth and development and (4) the exclusion of cyclic neutropenia, immunodeficiency and autoinflammatory syndromes.1 Fever peaks of up to 39–40°C periodically recur every 3–8 weeks for a period of 3–4 years, after which they usually spontaneously disappear; however, there are an increasing number of reports of adult-onset forms.2 Various authors have also observed that the syndrome can be associated with different combinations of other nonspecific symptoms, such as nausea, vomiting, headache, abdominal pain, malaise and arthralgia, which may complicate differential diagnosis.3 This review considers how to diagnose PFAPA syndrome, describes the debate concerning its pathogenesis and describes the suggested therapeutic approaches.
HOW TO DIAGNOSE PFAPA SYNDROME
No diagnostic tests for PFAPA syndrome are currently available. Normal white blood cells and normal acute phase reactants are usually found during the interfebrile periods, whereas patients have high white blood cell counts with a preponderance of neutrophils and high levels of inflammatory markers during febrile episodes.4 C-reactive protein levels seem to be higher in children with PFAPA syndrome than in those with bacterial tonsillitis, and an awareness of this may arouse suspicion of the syndrome in a child with a typical history or help to avoid the unnecessary use of antibiotics.5 Procalcitonin levels, a significant marker of bacterial infections, do not usually increase during febrile attacks, and serum levels of immunoglobulins A, G and M are also normal. The results of urine and blood cultures, chest radiography and liver function tests are normal. Only serum IgD levels may be slightly high.6
The diagnosis can be reinforced by excluding other causes of recurrent infectious, autoimmune or tumoral fevers.1 It has been clear since the first descriptions of PFAPA syndrome that cyclic neutropenia (characterized by a cyclic decrease in neutrophils with fever recurring every 3 weeks during the first year of life) should be excluded. Among the autoinflammatory syndromes characterized by lifelong and spontaneously relapsing bouts of fever and systemic inflammation without any apparent involvement of antigen-specific T cells, autoantibody production or signs of infection, only familial Mediterranean fever and mevalonate kinase deficiency syndrome need to be considered as their manifestations may overlap those of PFAPA syndrome. The first is characterized by periodic short-lasting febrile episodes combined with serositis and/or arthritis in patients of Arabian, Armenian, non-Ashkenazi Jewish or Turkish descent; the second is characterized by variably frequent, self-limiting febrile episodes of 3–7 days combined with arthralgia, diarrhea, splenomegaly, lymphadenopathy and an increase in the urinary excretion of mevalonic acid.7 As PFAPA syndrome includes oral aphthosis, 2 other disorders need to be considered for differential diagnosis: Crohn’s disease, in which mucosal ulcerations related to transmural inflammation can appear throughout the gastrointestinal tract, and Behçet’s disease, a systemic vasculitis in which panuveitis and different skin lesions are variably associated with larger recurrent oral ulcerations that are more painful and numerous than those associated with PFAPA syndrome.7
PATHOGENESIS OF PFAPA SYNDROME
The pathogenesis of PFAPA syndrome is still considered enigmatic because mechanisms of relapsing infections and immune dysregulation have both been considered likely. The evidence in favor of the possibility of an infectious trigger comes from geographically distinct patient cohorts, despite the fact that the prevalence of the disease seems to be similar throughout the world. The infectious agent most frequently reported to be related to PFAPA syndrome is Epstein-Barr virus, with variable patterns of reactivation, subverted immunological response kinetics or the intermittent suppression of antigens or epitopes.8 Some other microbiologic species have been associated with PFAPA syndrome in individual cases, but the absence of signs in most siblings or other close contacts of patients with confirmed PFAPA syndrome, the lack of seasonal clustering, the conflicting results of serological studies and the unsatisfactory response to antibiotics make the infectious hypothesis less probable.
The rapid response of fever to single doses of corticosteroids or cimetidine (acting as a suppressor of CD8+ T cells) suggests that immune dysregulation may be more likely. Stojanov et al9 studied cytokine secretion patterns in patients with PFAPA syndrome and found an increased release of interferon-γ and tumor necrosis factor-α during febrile attacks and, as in the case of many autoinflammatory syndromes, the levels of IL-1β, IL-6 and IL-18 were high at the time of fever onset. In 1999, Long10 suggested that PFAPA patients may have a group of cytokine-producing cells cyclically functioning under a supposed biorhythm (as in the case of cyclic neutropenia) and abnormally responding to different environmental antigens. Table 1 lists the potential pathogenetic mechanisms of PFAPA syndrome as suggested by the principal available studies.9–18
TREATMENT OF PFAPA SYNDROME
There is no consensus concerning the best remedy for PFAPA syndrome. The main therapies are essentially symptomatic and consist of single doses of corticosteroids: prednisone (1–2 mg/kg) or betamethasone (0.1–0.2 mg/kg) can abolish a febrile attack within a few hours. Kyvsgaard et al19 observed that the oral administration of prednisolone controlled febrile episodes in 87.5% of patients, although it was also associated with shorter interfebrile periods. Feder and Salazar20 found that cimetidine (150 mg twice a day for 6–12 months) interrupted fever attacks in only 27% of patients and that the prophylactic use of colchicine (0.5–1 mg/d) led to partial remissions with longer intervals between attacks. A meta-analysis of 14 studies published between 1999 and 2009 by Peridis et al21 revealed that antibiotics were ineffective; that surgical therapy (tonsillectomy with or without adenoidectomy) was more effective than antibiotics and cimetidine prophylaxis and that there was no statistically significant difference between treatment with corticosteroids and surgery, although they concluded that tonsillectomy was the most effective intervention for the long-term resolution of PFAPA syndrome as the use of corticosteroids did not prevent further febrile cycles and also shortened interfebrile intervals.
Despite the many efforts made to characterize PFAPA syndrome, there is still as much debate as there are controversies. Furthermore, the syndrome has a considerable socioeconomic impact on families because of the number of lost school or working days, and the physical and psychological costs of the disease. Further studies are needed to identify laboratory markers that would help to identify PFAPA patients and allow the best therapeutic approach to be defined. The possible double pathogenesis of PFAPA syndrome continues to raise a number of questions, with pros and cons related to its infectious or dysregulated immunological origin.
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