The Association Between Vitamin D Level and PFAPA Syndrome: A Systematic Review

Abstract

Periodic Fever, Aphthous Ulcers, Pharyngitis and Adenitis (PFAPA) Syndrome’s etiology is not well understood. The objective of this study is to explore the association between vitamin D level and PFAPA syndrome. A systematic review of all publications addressing the association between vitamin D level and PFAPA syndrome prior to May 2019 was conducted. Data were collected from online medical databases namely, PubMed, Ovid Medline, Embase, Cochrane Library, Google Scholar, and Scopus. The review adhered to the PRISMA statement and was performed in 3 main phases; an initial screening review of abstracts was performed, followed by a detailed review of full articles based on inclusion and exclusion criteria, and lastly a final review to extract data from selected articles. 3 prospective review-based and one case report articles were included with a total of 281 patients, 98 of whom were cases of PFAPA, while 183 were controls. Vitamin D levels were deficient in 27% of PFAPA group as compared with the control. Vitamin D supplementation was given as an initial treatment in 25/98 of the patients. Only 1 patient received it as a second treatment. After vitamin D supplementation, a marked reduction of the number of febrile episodes and modification of the mean duration were recognized. There may be an association between Vitamin D deficiency and a higher frequency of PFAPA episodes. Vitamin D supplementation in children with PFAPA may reduce the frequency of episodes and help manage the condition.

Introduction

PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) is a nonhereditary idiopathic chronic rare disease affecting preschool age children [1]. PFAPA syndrome represents the most common recurrent type of fever among children. This fever is characterized by episodes lasting 3–6 days (recurrent every 3–8 weeks) and is associated with at least one of the major symptoms: pharyngitis, cervical adenitis, and aphthous stomatitis [2]. Some additional features may be recognized but are not consistently noted, such as gastrointestinal symptoms, rash, headache, and arthralgia [3–6]. The diagnosis is made according to the clinical criteria in addition to the exclusion of other possible causes of recurrent fever.

The pathophysiology and etiology of this syndrome are still unknown; however, it rapidly responds to corticosteroid treatment, which suggests immune deregulation [7]. A narrative review of the literature reported that a low dose of corticosteroid is usually administered as a first-line treatment among children with PFAPA, although it cannot prevent episodes but only suppress flares [8].

Regarding basic science studies, it has been proven that the action of adaptive immunity is regulated by vitamin D; correspondingly, in the presence of a deficiency in vitamin D levels, the immune system displays an increased occurrence of autoreactive T cells [9, 10]. More recently, the role of vitamin D deficiency has been widely reported, apart from the nonclassical function of vitamin D, and its association with the immune system has been recognized [11]. However, only a few studies have explored a possible association of vitamin D deficiency and PFAPA attacks [1, 2, 12]. Therefore, the purpose of this study was to conduct a systematic review of all published articles reporting on the possible association between vitamin D levels and PFAPA syndrome.

Methods

Search Strategy

A systematic review of all articles published prior to May 2019 pertaining to the association between vitamin D level and PFAPA syndrome was conducted. The research was carried out in electronic databases, namely, PubMed, Ovid Medline, EMBASE, Cochrane Library, Google Scholar, and Scopus. The search strategy included the text words PFAPA. Vit D (all fields), PFAPA. Cholecalciferol (all fields), Vitamin D (all fields) in combination with each of [Periodic fever, Aphthus stomatitis, Pharyngitis and Cervical adenitis] (all fields), Cholecalciferol (all fields) in combination with each of [Periodic fever, Aphthus stomatitis, Pharyngitis and Cervical adenitis] (all fields), PFAP* (MeSh terms) in combination with Cholecalcif*(MeSh terms) and PFAP* (MeSh terms) in combination with Vit* D (MeSh terms). Articles published from the date of database inception to the end of May 2019 and written in English were included.

Study Selection

Initially, two authors (Sarah Faydhi and Hala M.Ali Kannawi) performed a complete and comprehensive database search to screen the articles’ titles, abstracts, and keywords. Then, two authors (Sarah Faydhi Hala M.Ali Kannawi) reviewed the full text to determine the eligibility of the articles and screened the references of these articles to find additional eligible articles. After selecting the eligible articles, the third author (Faisal Zawawi) reassessed the selected articles for final inclusion.

Statistical Analysis

All qualitative variables were reviewed, recorded, and stored in an electronic database.

Inclusion and Exclusion Criteria

We included publications discussing children 18 years or younger with PFAPA syndrome and measurements of vitamin D levels. Included studies had to have reported patients attended Pediatric Units after having excluded other causes of recurrent fever. We excluded articles reporting on patients who were older than eighteen or where the age group was not identified, patients who had infections and/or other causes of periodic fever, primary hyperparathyroidism, skeletal dysplasia, severe obesity, malabsorption disorders, endocrinological or renal diseases or patients who had already received vitamin D as a treatment for another underlying disease. Furthermore, articles that did not discuss the role of vitamin D in PFAPA syndrome were excluded. We also excluded articles with suspected duplicated data. Finally, commentaries, conference abstracts, letters, and replies were not considered eligible.

Study Measures

Cholecalciferol (vitamin D), also known as serum 25-hydroxyvitamin D, was considered the standard measure in our analysis and was reported in ng/mL.

Data Extraction and Quality Assessment

The first author (S.F.) extracted the data using a standardized tool for data extraction, and then the data were checked by the second (H.K.). The senior author (F.Z.) oversaw the methodology of data extraction and analysis. The extracted data were study design, period, and aim, first author, year of publication, age, sex, and the total number of participants, criteria of the PFAPA syndrome diagnosis, serum vitamin D level, the average duration of fever episodes, the average number of fever episodes, interval between episodes, seasonal variation and number of patients with vitamin D deficiency. A modified version of Downs and Black (DB) scale [13] were used to assess the quality of the articles that were found eligible. These articles did not have a high DB score that why caution should be exercised while interpreting these data.

Statistical Analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 21 and Microsoft Excel 14.3.6.

Results

Number of Studies and Study Designs, and Quality Assessment

The literature search yielded six articles, and two articles were added through screening the references of the selected articles. Eight articles were selected for full review; however, only four articles that met our inclusion and criteria were eligible for qualitative analysis. The selected articles were published between 2012 and 2019. Three of these articles were prospective studies and one case report study (Fig. 1). All the studies that were include had a low DB score reflecting a lower quality studies.

Fig. 1.

This is the PRISMA flowchart of the records that were identified through the literature search and pathway to inclusion in this study

Population and Demographics

The four included studies had a total of 281 patients, 98 of whom were cases, while 183 were controls, 107 of whom were girls, and their mean age was 4 ± 3 years (Table 1).

Table 1.

This table describes the studies included in this systematic review, their design and demographics

Author	Nalbantoğlu et al. [2]	Mahamid et al. [3]	Stagi et al. [4]	Rico Rodes et al. [5]
Country	Turkey	Israel	Italy	Spain
Participants, mean age (SD)	Case: 50 (50%), 4.00 ± 3.00 Control: 50 (50%), 4.00 ± 3.00	Case: 22 (52%), 4.20 ± 2.90 Control: 20 (48%), 4.30 ± 1.26	Case: 25 (18.12%), 3.60 ± 0.90 Control: 113 (81.88%), 4.90 ± 1.30	Case: 1 case, 23-month-old
Gender: (male, female)	Case: 28 (56%), 22 (44%) Control: 26 (52%), 24 (48%)	Case: 15 (68.18%), 7 (31.82%) Control: 12 (60.0%), 8 (40.0%)	Case: 19 (76.00%), 6 (24.00%) Control: 74 (56.49%), 39 (34.51%)	Case: female
Study design	Prospective study	Prospective study	Prospective study	Case report
D b scale [6]	13	9	8	N/A

Diagnosis and Investigation

PFAPA syndrome patients were diagnosed according to or based on their clinical manifestations and the Thomas or Euro-Fever PFAPA criteria; other possibilities of recurrent fever were excluded. A microbiological test (throat culture) was applied in two of four studies, and it was negative.

Treatment and Outcome

The study by Stage et al. [12] was the only prospective study that used vitamin D supplementation (400 IU/day for 6 months) to compare the patients’ status before and after supplementation. Vitamin D level, average duration of fever episodes and interval between episodes were considered before and after the supplementation. Furthermore, a case report by Rico Rodes [14] showed the results of using vitamin D supplementation of 400 IU (Table 2).

Table 2.

This table demonstrates the levels of vitamin D at presentation at the supplementation dose (if present) as well as vitamin D level after supplementation (if present) [3]

Author	Nalbantoğlu et al. [1]	Mahamid et al. [2]	Stagi et al. [12]	Rico Rodes et al. [14]
The dose of vitamin D supplement	–	–	Case: 400 IU of cholecalciferol Control: –	Case: 400 IU of cholecalciferol
Vitamin D level (ng/ml) before supplement	Case: 18.00 ± 10.00 Control: 30.00 ± 13.00	Case: 12.27  ± 11.02 Control: 20.34 ± 12.64	Case: 5 patients between 20 and 30 ng/mL, 20 (< 20 ng/mL) Control: –	Case: 23.7 ng/mL
Number of patients with vitamin D deficiency	Case: 38 (76.00%) Control: 20 (40%)	Case: 17 (77.20%) Control: 6 (30%)	Case: 5 patients (20%) insufficient level between 20 and 30 ng/mL, 20 (80%) showed deficient levels < 20 ng/mL Control: –	Case: 1
Vitamin D level (ng/ml) after supplement	–	–	Case: 9 patients (36.0%) sufficient vitamin D levels, 14 (56.0%) still had insufficient levels, 2 (8.0%) had deficient levels Control: –	Case: 40 ng/mL normal level *b
Average duration of fever episodes before vitamin D supplement (DAYS)	Case: 4 ± 1 *A 5 ± 1 *B Control: –	Case: 4.7 ± 1.12 Control: –	Case: 4.3 Control: –	Case: –
Average duration of fever episodes after vitamin D supplement(DAYS)	–	–	Case: 2.3 Control: –	Case: –
Interval between episodes before vitamin D supplement	Case: 6 ± 2A 5 ± 2B weeks Control: –	Case: 6.23  ± 2.1 weeks Control: –	Case: 25.3 days Control: –	Case: 6–8 weeksC
Interval between episodes after vitamin D supplement	–	–	Case: – Control: –	Case: 16 weeksD

*A: patients with normal 25(OH)D levels

*B: patients with insufficient 25(OH)D levels

C the flares increased after initiation of corticosteroid therapy

D only 2 episodes over the year post vitamin D supplement

Discussion

Over the past decades many publications have explored the association between vitamin D deficiency and/or supplementation with various infectious and inflammatory disorders, and although many studies have discussed the association of periodic fever with other medical conditions, the association between vitamin D deficiency and PFAPA attacks is largely unrecognized. As the incidence of PFAPA is rare, the current systematic review including three prospective studies and one case report providing up-to-date scientific evidence of the association between vitamin D deficiency and PFAPA attacks [1, 2, 12, 14].

Vitamin D Deficiency has been shown to be associated with various inflammatory and recurrent infection diseases. A systematic review published in 2012 suggested that vitamin D deficiency can impair self-tolerance by compromising immune cells, dendritic cells, T-lymphocytes, and Th1 cells among genetically predisposed subjects [11]. The findings demonstrated the genetic, environmental, and epidemiologic association of vitamin D levels with autoimmune/auto-inflammatory diseases such as multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and rheumatoid arthritis (RA) [11].

The inhibition of infiltration of Th1 cells and production of interluken-12 (IL-12) after the administration of 1.25(OH)2D3 (5 mcgr/kg on alternate days) or analogous compounds (BXL-219, MC 1288, Ro 63‐2023, Ro 26‐2) have shown based on animal models studies, This evidence has been demonstrated in MS [15, 16] T1DM [17–19] RA [20, 21] and in systemic lupus erythematosus (SLE) [22, 23].

Vitamin D Deficiency was also found in association with Familial Mediterranean fever (FMF). A study that was published in 2016 [41] demonstrated that vitamin D levels are lower in children with FMF compared with healthy controls, And they suggest that vitamin D levels should be carefully examined, and nutritional supplementation may be required in patients with FMF [24].

Other studies suggested that vitamin D is a physiologic factor that contributes to both innate and adaptive immunity through the vitamin D receptors (VDR) present in the nucleus of immune cells [25–27, 36]. The role of vitamin D as a regulatory factor of adaptive immunity was proven; in cases of vitamin D deficiency, autoreactive T cells are produced by the immune system [9, 10].

The majority of children with PFAPA syndrome have spontaneous symptom resolution with no long-term consequences when they get older, although a small percentage of those that have chronic symptoms may develop febrile episodes that are shorter in length and less frequent over time. In addition, different recent studies have identified a delayed onset of PFAPA syndrome in adulthood, with no discernible gender predominance. In reality, data on the precise prevalence of PFAPA syndrome in adults is scarce [28]. Previous studies showed that a deficiency of vitamin D may affect the course of immune-related disease activity [29, 30]. For instance, some studies showed that the vitamin D concentration may affect the immunological response in autoimmune diseases such as SLE and RA [31, 32]. Moreover, a meta-analysis including a systematic review of observation-based studies [33] showed significant evidence of a correlation between a low level of vitamin D and an increased risk of recurrent tonsillopharyngitis among both pediatric and adult groups.

Nalbantoğlu et al. [1], Mahamid et al. [2], and Stagi et al. [12] examined the effects of seasonal variations of Vitamin D levels on PFAPA patients and reported the intervals between episodes and the average duration of fever episodes. A throat culture or microbiological test to rule out infection was performed by both Mahamid et al. [2] and Rico Rodes et al. [14], Stagi et al. [12] reported a significant reduction in vitamin D levels in winter compared to in the summer season. Additionally, there was a significant effect of the seasonal variation on the fever episodes among 56.0% of the patients before vitamin D supplement administration. On the other hand, findings from other studies showed no significant variation in vitamin D levels during the summer and winter. This variation across the different studies might be attributable to multiple factors, such as individual or racial factors and the methods of vitamin D measurement.

Mahamid et al. [2] was the first to report that vitamin D deficiency (< 20 ng/ml) is a significant risk factor for PFAPA occurrence (77% Vs 30%) (Table 2). The other authors [1, 12] have recently documented the same results. Nalbantoğlu et al. [1] divided PFAPA patients into two groups according to their level of vitamin D (normal, insufficient), and they found that higher levels of 25(OH)D > 30 ng/ml (normal) correlated with low fever duration and a longer duration between the attack.

Vitamin D levels were restored in each study in both the control and cases. Additionally, the numbers of patients with vitamin D deficiency or insufficiency status were reported. It is important to note that Nalbantoğlu et al. [1], Mahamid et al. [2] and Stagi et al. [12] used vitamin D levels of 30 ng/mL as a cutoff value and defined vitamin D insufficiency as a level of vitamin D < 30 ng/ml and vitamin D deficiency as < 20 ng/ml whereas in the case study performed by Rico Rodes et al. [14] defined 40 ng/mL as a normal level of vitamin D.

Interesting vitamin D supplementation had a positive outcome on Rico Rodes et al. [14]. They reported a case of 23 months old girl who diagnosed with PFAPA syndrome. She had a multiple flares 6–8 weeks apart which increased frequently after the initiation of the corticosteroid therapy. During her course of the disease they notice deficiency in her vitamin D level but after the appropriate supplementation reaching the normal values they notice an improvement in her PFAPA flares status which had been decreased in number and severity to 2 mild episodes over the year (Table 2).

The supplementation and correction of Vitamin D levels were of interest and has been explored previously in association with various inflammatory and systematic diseases. Multiple reports studying patients with MS (113 cases) [34, 35], RA (44 cases) [36, 37], SLE (60 cases) [38], and systemic sclerosis (SSc) (51 cases) [39–42] demonstrated that the administration of cholecalciferol and/or alfacalcidol (2 mcg/d) to patients had no improvement or effect in the symptoms of the disease or the number of relapse episodes. On the other side, these studies did not exhibit any positive effect in relation to the immunological evolution of the disease or its clinical onset after the supplementation [38, 43–45]. Contrarily various studies carried out on T1DM indicated a positive outcome effect of the disease, protected the β-cell function and reduced the insulin requirement after the administration of 0.5 mcg/day of vitamin D [46, 47].

In contrast to the other prospective studies, for the first time, Stagi et al. [12] reported data about the response of PFAPA patients to vitamin D supplementation. The average duration of fever episodes was 4.3 days, while the interval between episodes was 25.3 days in PFAPA patients before the administration of vitamin D. Then, 400 IU of vitamin/day was established from November to May for all PFAPA patients, for a mean period of 7.4 ± 1.1 months. After vitamin D supplementation, although only 36.0% of the PFAPA patients reached sufficient vitamin D levels, 56.0% had insufficient levels, and 8.0% had deficient levels, Stagi et al. [12] observed a decrease in the duration of fever episodes after vitamin D administration to 2.3 days in 36% of the cases. They also noted that enhancing the vitamin D status in PFAPA subjects significantly decreased the number of PFAPA febrile episodes, but unfortunately, nothing about the interval between the episodes was mentioned. However, this response to vitamin D supplementation among PFAPA patients can support the idea of considering vitamin D as an immune-regulatory factor in PFAPA syndrome and suggests a possible therapeutic role as well.

Conclusion

Although PFAPA syndrome is consider as one of the self-limited condition in childhood, its impact on social lives of children and families can be remarkable in many cases. Further studies with larger patient populations are needed to confirm the association between vitamin D deficiency and PFAPA syndrome episodes.

Authors’ Contributions

Sara A. Faydhi Data collection, Data analysis, Manuscript writing, study design, revision editing, final manuscript review and production. Hala M.A. Kanawi Data collection, Data analysis, Manuscript writing and final manuscript review and production. Talal Al-Khatib Study Design, review of analysis, revision editing, final manuscript review and production. Faisal Zawawi Senior Author, Data collection, Data analysis, Manuscript writing, Study design, revision editing, final manuscript review and production.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

None of the authors have a conflict of interest.