Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome.

Luca Cantarini,Isabella Patisso,Lucia Cerrito,Mauro Galeazzi,Ludovico Luca Sicignano,Antonio Vitale,Raffaele Manna,Gabriele Cevenini,Bruno Frediani,Elena Verrecchia,Donato Rigante,Claudia Fabiani,Giacomo Emmi

doi:10.3389/fimmu.2017.01018

Abstract

To identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO). We enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data. According to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92; p < 0.0001), fever attacks associated with erythematous pharyngitis (OR = 231; p < 0.0001), increased inflammatory markers during fever attacks (OR = 588; p = 0.001), and the lack of clinical and laboratory signs of inflammation between flares (OR = 1202; p < 0.0001). These variables were considered for a diagnostic model which accounted for their OR values. The diagnostic accuracy of the proposed set of criteria corresponded to an area under ROC curve of 0.978 (95% CI 0.958-0.998), with a model sensitivity and specificity equal to 93.4% (95% CI 87.5-96.5%) and 91.7% (95% CI 82.8-96.7%), respectively. we have provided herein a set of clinical diagnostic criteria for adult-onset PFAPA syndrome. Our criteria represent an easy-to-use diagnostic tool aimed at identifying PFAPA patients among subjects with FUO with a high-predictive potential, as shown by its very high sensitivity and specificity.

Highlights

Aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome belongs to the spectrum of multifactorial autoinflammatory diseases (AIDs) and is characterized by spontaneous flares of systemic inflammation characterized by fever and other clinical manifestations, especially cardinal signs described by the PFAPA acronym [1]
We looked for clinical variables that can identify patients with adult-onset PFAPA syndrome among patients presenting with fever of unknown origin (FUO)
We analyzed the occurrence of inflammatory features in patients with a clinical picture consistent with adult-onset PFAPA syndrome, being excluded all the known causes of recurrent fever, as well as in patients consecutively visited in our Units because of FUO during a 6-month period

Summary

Introduction

Aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome belongs to the spectrum of multifactorial autoinflammatory diseases (AIDs) and is characterized by spontaneous flares of systemic inflammation characterized by fever and other clinical manifestations, especially cardinal signs described by the PFAPA acronym [1].To date, the pathogenesis of this syndrome remains still obscure, but studies aimed at assessing immunological mechanisms, supported by therapeutic evidences [2, 3], have highlighted an abnormal interleukin-1 release in response to many environmental triggers, which associates PFAPA syndrome to other hereditary periodic fever disorders [4, 5]. Aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome belongs to the spectrum of multifactorial autoinflammatory diseases (AIDs) and is characterized by spontaneous flares of systemic inflammation characterized by fever and other clinical manifestations, especially cardinal signs described by the PFAPA acronym [1]. In addition to fever (often achieving and overcoming 40°C), aphthous stomatitis, pharyngitis, and cervical adenitis, many other clinical manifestations may enrich the clinical framework of PFAPA patients, including abdominal pain, headache, nausea, skin manifestations, and arthralgia [1, 8,9,10]. The treatment of PFAPA patients is based on intermittent corticosteroid administration, as patients are generally responsive to a single dose of a corticosteroid given at the onset of febrile flares [1, 12, 14, 19, 20]

Methods

Results

Conclusion