Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome

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Abstract

Background

The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease characterized by regularly recurrent fever episodes due to seemingly unprovoked inflammation.

Objective

To assess serum 25-hydroxyvitamin D [25(OH)D] concentrations in children with PFAPA syndrome and evaluate longitudinally the effect of wintertime vitamin D supplementation on the disease course.

Study design

We have evaluated 25 Italian patients (19 males, 6 females, aged 2.4–5.3 years), fulfilling the Euro-Fever PFAPA criteria. For each patient, we recorded demographic and anthropometric data, clinical manifestations, serum calcium, phosphate, and 25(OH)D. After 400 IU vitamin D supplementation during wintertime, clinical and auxological characteristics, calcium, phosphate, and 25(OH)D levels were re-evaluated. Data were compared with a sex- and age-matched control group.

Results

PFAPA patients showed reduced 25(OH)D levels than controls (p < 0.0001). Regarding the effect of seasons on vitamin D, winter 25(OH)D levels were significantly reduced than summer ones (p < 0.005). Moreover, these levels were significantly lower than in healthy controls (p < 0.005), and correlated with both fever episodes (p < 0.005) and C-reactive protein values (p < 0.005).

After vitamin D supplementation, PFAPA patients showed a significantly decreased number of febrile episodes and modification of their characteristics (mean duration of fever episodes, p < 0.05; number of febrile episodes per year p < 0.005).

Conclusions

Deficient and insufficient vitamin D serum levels were found in most children with PFAPA syndrome, and hypovitaminosis D might be a significant risk factor for PFAPA flares. However, vitamin D supplementation seems to significantly reduce the typical PFAPA episodes and their duration, supporting the role of vitamin D as an immune-regulatory factor in this syndrome.

Introduction

The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, first described as a clinical entity in 1987 [1], belongs to the group of autoinflammatory diseases [2]. This condition is an idiopathic chronic disease of non-hereditary origin, primarily affecting pre-school children, characterized by regularly recurrent fever episodes, lasting for 3–6 days with a remarkable clockwork periodicity of 3–8 weeks in approximately 50% of patients, due to seemingly unprovoked inflammation [2]. By definition, a constellation of cardinal signs (pharyngitis, cervical adenopathy, aphthous stomatitis) and systemic symptoms (headache, abdominal pain, vomiting, malaise, skin rash, etc.) appear in each PFAPA inflammatory attack, which is typically observed in less than 5 year-children who have no sign of respiratory tract infections [3]. At present, no specific biomarkers are available to help the diagnostic evaluation [4]. As in other periodic fever syndromes, there is a marked increase in C-reactive protein (CRP), other acute phase reactants, and white blood cell count [5], which are indicative of a prominent systemic inflammatory response. In children with PFAPA syndrome, these indicators return to normal levels when symptoms subside [5], [6]. Therefore, in order to corroborate the diagnosis, it is necessary to rule out the monogenic periodic fever syndromes that may show overlapping features with PFAPA syndrome [6].

Vitamin D plays an important role in calcium balance, which is largely a function of calcium dietary intake, intestinal absorption, renal excretion, and bone remodeling [7], [8]. More recently, vitamin D has gained attention for a plethora of other crucial benefits, and emerging evidence suggests that vitamin D plays a key-role in immunity regulation [8]. In fact, vitamin D receptors are found on several immune cells, and vitamin D metabolites seem to modulate T cell proliferation and dendritic cell function [9], [10]. Hence, vitamin D deficiency may represent a risk factor for the development of autoimmune and other chronic diseases [8], [11], because of its potential role as an immune-regulatory agent.

Serum 25(OH)D is the most commonly used indicator of vitamin D status, reflecting dietary intake from vitamin D2 (ergocalciferol) and cutaneous synthesis of vitamin D3 (cholecalciferol) [12]. Vitamin D status in PFAPA children has been evaluated in only one study, which did not consider the effects of vitamin D supplementation [13]. The purpose of our study was to assess serum 25(OH)D in children with PFAPA syndrome and evaluate longitudinally the effect of wintertime vitamin D supplementation on the disease course.

Section snippets

Patients and methods

We have consecutively evaluated 25 Italian children (19 males, 6 females, mean age 3.6 ± 0.9 years, range 2.4–5.3 years), after having excluded other causes of recurrent fever. All patients attended the Pediatric Units of different Tuscany Hospitals (Pediatric Unit of Villamarina Hospital, Piombino, Livorno; Pediatric Unit of Mugello's Hospital, Borgo san Lorenzo, Florence; Rheumatology Section, Transition Clinic, University of Florence, Florence; and Health's Sciences Department, Anna Meyer

Statistical analysis

The characteristics of the study population were described through frequency distributions for categorical variables and through means and standard deviations (SDs), medians, and range for continuous variables. The crude association of vitamin D status and the other categorical variables was assessed through chi-square test and Fisher's exact test. The crude association of vitamin D status and continuous variables was assessed through Wilcoxon's rank-sum test and Kruskal–Wallis test, since all

Results

No statistically significant differences were found between patients with PFAPA syndrome and the control group with regards to height (−0.2 ± 0.7 vs 0.1 ± 0.9, p = NS), and body mass index (BMI) SD (0.9 ± 1.3 vs 0.6 ± 1.1, p = NS). The median age at onset of symptoms was 30 months (range: 17–58 months). The mean duration of fever episodes was 4.3 days (95% CI: 3.5–5.3), and the mean duration of intervals between fever episodes was 25.3 days (95% CI: 20.4–30.1). The number of fever episodes per year was 8.9 ±

Discussion

Our data confirm the results of Mahamid et al. who discovered significantly decreased 25(OH)D levels in children with PFAPA syndrome, compared with a control group, showing a correlation between 25(OH)D levels and CRP, and hypothesizing that vitamin D deficiency might be a significant risk factor for PFAPA febrile episode recurrence [13]. Indeed, our patients with PFAPA syndrome displayed reduced serum 25(OH)D levels, apparently related with the number of febrile episodes and CRP, disclosing a

Conclusions

In conclusion, deficient and insufficient vitamin D serum levels have been found in most children with PFAPA syndrome. Hypovitaminosis D can be a significant risk factor for PFAPA episode recurrence. In addition, vitamin D supplementation seems significantly to reduce PFAPA febrile flares and their duration, proving the relevance of vitamin D as a promoter of T cell regulation in this syndrome.

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