Recurrent fever: An epidemic in a pandemic

ABSTRACT

Introduction: Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome is the most common periodic fever syndrome in children. It is a benign self-limiting multifactorial disorder with an estimated incidence of 2.3/10000 children up to 5 years of age. Year 2020 was dramatically affected by the Covid-19 pandemic, with a yet undefined impact on several aspects of child health. Objectives: To describe the demographic and clinical features of pediatric patients with recurrent febrile episodes referred to a single centre, with a focus on cases with onset in 2020. Methods: Patients referred to the Pediatric Immunology and Pediatric Rheumatology departments between 01/01/2015 and 01/ 05/2021 for recurrent fever without an infectious cause were included in the study. Demographic, clinical and laboratory features were retrospectively reviewed and compared between patients with fever onset before and after January 1st, 2020. For the classification of PFAPA, both the modified Marshall criteria and the Eurofever/ PRINTO criteria were used. Resolution of PFAPA was defined in presence of a 3-month fever-free interval. For statistical analysis, Mann-Whitney U test and Fisher's exact test were used as appropriate. Results: 84 patients were included;33 were female, 82 were white. Median age at onset was 3.7 years (IQR 2-4.6, range 0.3- 12.9). Median length of follow-up was 1.3 years (IQR 1.1-2.3, range 0.5-6.4 years). 57/84 (68%) patients met the modified Marshall criteria, 72/82 (88%) patients met the Eurofever/ PRINTO criteria for PFAPA. Thirty-nine patients had disease onset between 01/2015 and 12/19, while 45 patients in 2020. One patient with onset in 2015 and resolution in 2018, restarted presenting recurrent fever in January 2020. In 29 patients recurrent fever resolved during the follow-up, 39 in the 2015-2019 cohort and 10 in the 2020 cohort. Median follow-up since onset was 2.4 years in the 2015-2019 group and 1.1 years in the 2020 group. While median age at onset was not significantly different in the two groups (3.2 vs 3.8 years), in patients with onset in 2020 median time to referral was shorter (14.3 vs 7.5 months, p<0.0001) and recurrent fever episodes tended to resolve faster (median 2.3 vs 0.9 years, p<0.0001). Aphtous stomatitis and lymphadenitis appeared more common in patients with onset before 2020 (64% vs 32%, p=0.0062 and 84% vs 58, p=0.0322 respectively). Duration of fever episodes and intercritic interval, periodicity, prevalence of pharyngitis, abdominal pain and arthralgia were not significantly different between the two cohorts. (Table Presented) Conclusion: We observed an increase in referrals for recurrent fever with onset during 2020. Demographic and clinical features did not significantly differ between patients with onset in 2015-2019 and patients with onset in 2020, with the exception reduced occurrence of aphtous stomatitis and lymphadenitis, and faster referral and resolution for the latter. Whether an increase in parental attention and concern for fever episodes, or environmental factors, including SARSCoV- 2, contributed to the increase of referrals for recurrent fever still needs to be clarified.