Surveillance of Periodic Fever Syndromes in Canada
Authors: Dancey P , Benseler S , Miettunen P , Turner L , Gattorno M , Laxer R M. , Junker A 
Published: September 2022

Abstract
BACKGROUND: Periodic fever syndromes (PFS) represent a group of rare, inflammatory disorders, which have their onset in childhood, and are associated with significant lifelong morbidity, and at times, increased mortality. The majority of affected children have recurrent, self-limited inflammatory episodes with unprovoked fever. The severe inflammatory state during an attack causes signs and symptoms in one or more organ systems. The Canadian Pediatric Surveillance Program (CPSP) studies relevant conditions of public health importance that are of such low incidence or prevalence that national ascertainment of cases are needed. Conditions that are studied share a high disability, morbidity and economic costs to society, despite the low frequency. More than 2400 pediatricians including relevant subspecialists, have been enrolled as CPSP participants. This program provides an ideal mechanism for surveillance of PFS in Canada.
OBJECTIVES: To estimate the incidence of periodic fever syndromes in the Canadian paediatric population, to describe the patterns of presentation, and to raise awareness in the medical community.
DESIGN/METHODS: This study was initiated through the Canadian Paediatric Surveillance Program (CPSP), and was carried out over a three year period ending in September 2014. The case definition included patients less than 18 years of age presenting with a newly diagnosed periodic fever syndrome (PFS). Conditions under surveillance included Familial Mediterranean fever (FMF), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulin D syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), and Undefined periodic fever syndromes. The study protocol outlined established clinical and/or genetic criteria for diagnosis. Participating pediatricians and pediat-ric subspecialists across the country were sent monthly reporting forms. Detailed questionnaires were completed by physicians who report a recent diagnosis. Submissions were screened for accuracy and confirmed cases then entered into a database.
RESULTS: Between September 2011 and August 2014 a total of 221 cases of PFS were reported. Detailed questionnaires were completed on 194 (88%), from which 13 were excluded. Of the 181 confirmed cases, 85 (47%) were PFAPA, 72 (40%) were undefined PFS, 17 (10%) were FMF, and the remaining 6 cases were CAPS, TRAPS, and HIDS. The mean age at diagnosis was 5.5 years (range 12 months – 16 years). On average symptom onset occurred 2.5 years before diagnosis (range 1-4 years). The majority of reporting physicians were rheumatologists (58%), and paediatricians (36%). Cases were identified in all provinces across Canada with the majority (103, 57%) from Ontario. For the 72 undefined PFS cases the reporting physicians described 36% as PFAPA-like, 10% FMF-like, 5% HIDS-like, 3% CAPS-like, and 1% TRAPS-like. Such cases had features of the specified PFS but either did not meet the full criteria, or confirmatory tests were not available at the time of reporting. Among all cases reported in the study, 58% had genetic testing completed as part of their diagnosis. The majority of cases without any genetic testing had been diagnosed as PFAPA.
CONCLUSION: Periodic fever syndromes represent rare forms of autoin-flammatory disease, which affect many Canadian children. This CPSP study identified that the most common PFS diagnosed was PFAPA followed by undefined PFS and FMF. CAPS, HIDS, and TRAPS were rarely diagnosed. Children with PFS were seen by multiple physicians over an average of two to three years before a diagnosis was made. It is hoped that increased awareness of these rare conditions will facilitate earlier diagnosis and the initiation of effective treatments for these children.