PFAPA Patients Research Articles

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome (PFAPA): A Clinical Challenge for Primary Care Physicians and Rheumatologists

Objective: To show the different physician's approaches and the difficulties in the diagnosis and management of the Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) syndrome, and to quantify the impact of the disease on the families and on the healthcare system.Study Design: Retrospective analysis on 40 patients diagnosed with PFAPA, focusing on the clinical phenotype, the process of diagnosis, and the management of the febrile episodes. The direct and indirect annual economic cost related to PFAPA in the period preceding the diagnosis were also investigated.Results: The median age of patients at disease onset was 1.75 years and the median time to diagnosis was 14.5 months. During the diagnostic process, only 45% of our patients was firstly addressed to rheumatologic consultation, 32.5% to otorinolaryngologist (ORL), and 22.5% to immunologic consultation. Genetic investigations were performed in the 20% of the cohort. Overall population experienced a median of 60 annual days of fever and, during the critical phase, 40% of patients received more than 5 cycles of antibiotic/year. Seventy five percent required laboratory investigations, 18 (45%) needed to access to emergency department and 15 (37.5%) have been hospitalized. The annual mean direct cost was 1659.5 € for each patient, and the estimated mean indirect cost was 5811.6 € for each parent.Conclusion: Despite a benign clinical course, PFAPA syndrome is associated with a significant impact on the patients, their families and the national healthcare system. PFAPA patients require a large number of medical examinations and laboratory or instrumental investigations during the diagnostic approach and often receive inappropriate treatments. Therefore, we suggest the necessity of a greater awareness and knowledge of the disease among primary care physicians and, finally, of the adoption of more specific diagnostic criteria.

Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. Our new criteria are useful for diagnosing PFAPA.

Immunogenicity and side-effects of the inactivated hepatitis A vaccine in periodic fever, aphthous stomatitis, pharyngitis, and adenitis patients.

The aim of this study was to compare the immunogenicity and side-effects of hepatitis A virus (HAV) vaccination between periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) patients and healthy controls who have not been previously exposed to HAV. A prospective observational study was carried out of 28 PFAPA patients and 76 controls who received two doses of the vaccine. Immunogenicity was expressed as seroconversion and seroprotection rates; mean HAV-immunoglobulin G concentration was measured at 0, 1, 7 and 18months. Side-effects were defined as incidence of adverse events and the effect of vaccination on PFAPA symptoms. All participants were seronegative and seroconverted at 1month. One month after primary vaccination, 92.9% of PFAPA patients and 77.6% of the controls attained seroprotection, while the rates increased to 100% and 96.1%, respectively, 1month after the second dose. Seroprotection rates remained adequate 1year after completion of vaccination. In conclusion, two doses of the inactivated HAV vaccine are well-tolerated and effective in children with PFAPA.

High Prevalence of Autoantibodies Against Monomeric C Reactive Protein (CRP) in Children with PFAPA Syndrome.

SummaryPFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome is an autoinflammatory disorder of unknown etiology. The aim of our study was to evaluate whether the presence of anti-mCRP autoantibodies (anti-mCRP) might possibly contribute to systemic inflammation during PFAPA flares. We carried out anti-mCRP testing (in-house ELISA) in a single-center, prospective cohort of 30 PFAPA patients (12 girls). We found a high prevalence (43.3%) of anti-mCRP antibodies in PFAPA patients during their febrile episodes, which implies the possible involvement of anti-mCRP antibodies in PFAPA pathogenesis.

Towards a new set of classification criteria for PFAPA syndrome

BackgroundDiagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall’s criteria, but no validated evidence based classification criteria for PFAPA has been established so far.MethodsA multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria.In the second phase the new classification criteria and the modified Marshall’s criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance.ResultsThe Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall’s criteria when applied on our cohort of patients.ConclusionOur work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.

The PFAPA syndrome: current paradigm and a clinical case description

In the last decades, hereditary autoinflammatory diseases / syndromes (HAIDS) are in the focus of research and practical interests of clinicians. Common characteristics of all known HAIDS include periodic fever and systemic inflammation in combination with other clinical syndromes of certain persistence. According to current understanding, HAIDS are considered the primary immunodeficiency states, related to genetic disruption of the interplay between inflammation regulators that arise in the absence of any pathogen. Many HAIDS manifesting at childhood are associated with severe natural course and serious prognosis. An exception from this is one of the most prevalent HAIDS in children, the PFAPA syndrome, which has a favorable outcome. The term “PFAPA syndrome” is an acronym of the main clinical manifestations, such as Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis. Given the early age of its manifestation, coinciding with the time of a child's socialization, PFAPA patients can be mistakenly follow-up within the group of “frequently sick children” for many years, with high medication load. The disease is triggered by genetically determined dysregulation of congenital immunity associated with excessive production of inflammation mediators (IL-1, TNFα, IL-6, IL-12p70, etc.), with no signs of autoimmunity (autoantibodies, autoreactive T-lymphocytes). There are no specific biological markers for the PFAPA syndrome, therefore, the diagnosis is largely based on the knowledge of the main clinical symptoms of the disease, described in detail by G.S. Marshall (1987), and on the high efficacy of glucocorticosteroids. The authors present a clinical case of a 4 year and 3 month's child who suffered from repeated attacks of PFAPA-syndrome from the age of 1.5 years that recurred at a constant rate every 1.5 to 2 months. Initially, all PFAPA episodes were interpreted as manifestations of a complicated acute respiratory viral infection. Conventional therapy was ineffective. Medical examination of the parents showed chronic tonsillitis in the mother; her subsequent tonsillectomy had no effect on the course of the disease in the child. Only by the age of four, the diagnosis of the Marshall syndrome was first suspected and then confirmed. With a diagnostic and therapeutic purpose, prednisolone was administered at a dose of 1.5 mg/kg body weight with prompt normalization of the body temperature and improvement of the patients' general condition. Assessment performed at 6 months after this confirmed the adequacy of the treatment strategy, while the frequency of PFAPA episodes reduced and they became mild. Conclusion: It is necessary to increase doctors' awareness of HAIDS and of PFAPA syndrome in particular, that would ensure timely diagnosis and proper treatment.

Risk factors for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a case-control study.

Maternal smoking and lack of breastfeeding, known risk factors for common childhood infections, were more common in patients with PFAPA syndrome than in matched controls. Environmental factors may be important in the pathogenesis of PFAPA syndrome and should be evaluated in future studies. What is Known: • The pathogenesis and genetics of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome remain unsolved. • PFAPA syndrome has been shown to cluster in families. What is New: • Maternal smoking and lack of breastfeeding are more common in patients with PFAPA syndrome than in the controls. • Environmental risk factors may be important in the pathogenesis of the syndrome.

Tonsillar antimicrobial peptide (AMP) expression profiles of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) patients

IntroductionPFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) is the most frequent non-infectious cause of high fever observed among the European child population. While its cause is still not yet fully identified, PFAPA patients were previously shown to have altered tonsillar microbiome composition. Our study hypothesized that this is associated with a change in antimicrobial peptide (AMP) expression levels, as in the case of Crohn's disease which is another autoinflammatory disorder. Methods and materialsThe tonsil specimens were isolated from seven patients with PFAPA syndrome, and six patients with group A beta-hemolytic streptococcal (GAβHS) recurrent tonsillitis. Tonsillar expression levels of human beta-defensin 1-2, cathelicidin, ribonuclease-7, and liver expressed antimicrobial peptide-1 were monitored by immunohistochemistry (IHC). Expression levels were scored using semi-quantitative analysis method and were statistically analyzed by Two-Way Repeated Measures Analysis of Variance test. ResultsOur results showed no significant difference in AMP expression levels between PFAPA and GAβHS patients. Immunolocalization of human beta-defensin 1 was different between the two groups; expressed at higher levels on tonsil surface epithelium (SE) than lymphoid interior (LI) in PFAPA patient group, while this was not evident in GAβHS patients group. ConclusionsOur results suggest that, PFAPA patients may be associated with altered AMP expression as in other autoinflammatory diseases. Future studies with subjects without any inflammatory condition are required for more precise conclusions.

Unraveling the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis through genetic, immunologic, and microbiologic discoveries: an update.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is considered the most common periodic fever syndrome of childhood. Although it was first described three decades ago, the pathogenesis has been poorly understood. Recent studies on the heritability and immunology of the disorder have begun to shed light into the mechanisms of this autoinflammatory disorder. This review will focus on the pathogenesis of PFAPA, especially as it pertains to the genetic susceptibility, tonsillar immunology, and the role of the microbiome. Recent literature provides insights into the heritability, potential genetic modifiers, and the immunologic and microbiological profile of the tonsils in this syndrome. Evidence is mounting that PFAPA is inherited as a complex genetic disease. Furthermore, tonsillectomy is curative in the majority of patients, including those who do not meet the complete clinical criteria for PFAPA. The tonsils in PFAPA patients may exhibit unique immunologic and microbiological features. The goal of this review is to outline these new developments.

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

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.

Unique histologic features of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome

The objective of this study is to compare the histology and immune cell composition of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome to those from patients with obstructive sleep apnea (OSA). Patients with PFAPA and age-matched controls with OSA who had undergone tonsillectomy at Vanderbilt Children's Hospital were recruited. After informed consent, archival paraffin-embedded, formalin-fixed tonsil tissues were obtained. Sizes of major histologic regions were measured. Cores of germinal centers, crypts, and squamous epithelium were assembled on a tissue microarray for immunohistochemical staining and digital image analysis. Features of tonsils from PFAPA and OSA patients were compared with Wilcoxon signed-rank test. Samples from 16 cases with PFAPA and 16 controls with OSA were evaluated. Tonsils from PFAPA cases had significantly smaller germinal centers (0.18 vs. 0.47mm2, p=0.001) and wider squamous epithelia (176 vs. 138μm, p=0.008) than those of OSA patients. The percentages of B and T lymphocytes and myeloid cells were comparable in germinal centers, crypts, and squamous epithelia from PFAPA and OSA patients. Longer time from the last febrile episode in PFAPA cases was associated with larger germinal center area (Spearman's rho=0.61, p=0.02). We found differences in the sizes of germinal centers and squamous epithelia in tonsils of patients with PFAPA and OSA, but the cellular compositions within these areas were comparable. Our results suggest that tonsils from patients with PFAPA change histologically over time with enlarging germinal centers following a febrile episode. Additional studies are needed to understand the pathogenesis of PFAPA.

Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome Is Associated with a CARD8 Variant Unable To Bind the NLRP3 Inflammasome

Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a relatively common autoinflammatory condition that primarily affects children. Although tendencies were reported for this syndrome, genetic variations influencing risk and disease progression are poorly understood. In this study, we performed next-generation sequencing for 82 unrelated PFAPA patients and identified a frameshift variant in the CARD8 gene (CARD8-FS). Subsequently, we compared the frequency of CARD8-FS carriers in our PFAPA cohort (13.9%) with a healthy local population group (3.2%) and found a significant association between the CARD8-FS polymorphism and risk for PFAPA syndrome (p = 0.012; odds ratio: 4.96 [95% confidence interval, 1.33-18.47]). Moreover, CARD8-FS carriers display a distinct PFAPA phenotype that is characterized by a higher prevalence of symptoms out of flares and oral aphthosis (both p = 0.02 compared with PFAPA patients without the frameshift variant). CARD8 encodes a protein component of the NLRP3 inflammasome, which plays an important role in inflammation and contributes to the pathology of various autoinflammatory diseases. We found that the CARD8-FS variant led to a truncated CARD8 protein lacking the FIIND and CARD domains. As a result, the mutant CARD8 protein lost the ability to interact with the NOD domain of NLRP3. In summary, these results identify a new CARD8 variant associated with PFAPA and further suggest that disruption of the interaction between CARD8 and NLRP3 can regulate autoinflammation in patients.

Zespoły gorączek okresowych u dzieci w praktyce oddziału pediatryczno-zakaźnego – doświadczenia ośrodka wrocławskiego

IntroductionFever is one of the top reasons for pediatric visits. Periodic fever syndroms (PFSs) are rare but increasingly recognized disorders and represent a new challenge for Polish doctors. The aimTo evaluate clinical picture, treatment results, disease outcome and its’ impact on the quality of life of patients with PFSs, based on a 10-year single center experience. Materials and MethodsFifty-five patients diagnosed with PFSs in 2006–2015 were included in the study. Diagnostic and therapeutic algorithms, definitions of treatment response and remission were established. The patients were followed up via hospital and outpatient visits, and telephone consultations. ResultsPeriodic fever, aphtous stomatitis, pharyngitis and adenitis (PFAPA) syndrome was diagnosed in 47 and monogenic periodic fever syndromes (MPFSs) in 8 patients.: In PFAPA syndrome, the most common symptoms accompanying fever were pharyngitis, cervical adenitis and aphtous stomatitis, in MPFSs: abdominal pain and diarrhea. In 80% of cases, ibuprofen was more effective than paracetamol in symptomatic treatment of febrile episodes. Steroids aborted PFAPA flares in 90.9% of the treated patients, tonsillectomy was effective in all operated children. Full remission (≥12 months) was reached by 14 PFAPA patients and 1 patient with MPFS, who was the only one to receive biological treatment. In most cases, after the diagnosis of a PFS, the use of antibiotics, number of hospitalizations and blood draws and the level of general parental fear about the child's health have decreased. ConclusionsPolish doctors’ readiness to recognize periodic fever syndromes allows avoidance of unnecessary antibiotic use and has a positive impact on the quality of life of patients and their families. While PFAPA syndrome is a mild, self-limiting disease, PFSs are chronic conditions that require effective prevention of amyloidosis.

Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome?

IntroductionPFAPA syndrome is the most frequent periodic fever syndrome in non-Mediterranean patients. The pathogenesis is unclear and the treatment is purely symptomatic and not standardized. The aim of this study was to assess colchicine's efficacy as prophylactic treatment in PFAPA syndrome and to identify factors able to predict response to treatment. MethodsWe performed a retrospective, multicentric, cohort study of PFAPA patients under colchicine prophylaxis. PFAPA diagnosis was established according to Feder's criteria. Medical records were reviewed and analyzed for demographic, clinical and laboratory data. We distinguished one responder's group, defined as patients who had no more or twice fewer crises under colchicine and another one of non-responders. Subgroup analyses were performed using non-parametric Mann-Whitney test for quantitative data and calculating odds ratio and confidence interval for qualitative data. Difference between the two groups was considered significant for P-value<0.05 or a confidence interval different from 1. Results-conclusionTwenty children, 65% of whom were boys, were analyzed. Their mean age at disease onset was 2.3±1.5 years. Among the nine responder patients, five were MEFV (71%) heterozygotes: M694V mutation in four and V726A once. Heterozygous MEFV gene mutation tended to be more frequent in the responders group (71% versus 43%; OR=0.3 [0.03–2.7]). Non-responder patients had more chronic fatigue (82% versus 33%; OR=9 [1,14–71]) and had more oral aphtosis (82% versus 11%; OR=36 [1,7–141]) than the responders ones. Although not significant, colchicine treatment appeared more effective in patients with less complete PFAPA phenotype and MEFV heterozygosity.

Looking back at the diagnosis of PFAPA: a retrospecitve analysis of a prospective cohort study

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever syndrome of childhood. The original diagnostic criteria were introduced in 1989. However, published studies show large heterogeneity in PFAPA patients, promting attempts at refining the criteria.

Microbes of the tonsils in PFAPA (Periodic Fever, Aphtous stomatitis, Pharyngitis and Adenitis) syndrome - a possible trigger of febrile episodes.

Periodic Fever, Aphtous stomatitis, Pharyngitis, and Adenitis (PFAPA) is a childhood febrile syndrome that is often cured by tonsillectomy (TE). We hypothesized that microbes present in the tonsils may act as a trigger for the activation of inflammasomes and investigated the microbiology of the tonsils in PFAPA patients and controls. We recruited 31 consecutive children who underwent TE due to PFAPA; 24 children who underwent TE due to other reasons served as controls. We cultured all the samples for bacteria, mycobacteria, yeasts, and viruses and used PCR for 15 viruses. Also biofilm formation and histologic findings were identified. The samples of the patients yielded Candida albicans more often than did the controls (16 vs 0%, p = 0.003). Staphylococcus aureus occurred in only 10% of the patients, but in 38% of the controls (p = 0.01). Varicella zoster and Herpes simplex viruses occurred less often in patients than in controls. Biofilm was present in 55% of PFAPA tonsils, but in only 24% of the controls (p = 0.03). The microbes found in the tonsils of PFAPA patients showed significant differences from those of controls. This may in part explain the efficacy of TE in PFAPA.

Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients.

PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children's Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture.

THU0374 Vitamin D Levels and Effects of Vitamin D Replacement in Children with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome

BackgroundThe periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, is an autoinflammatory disease characterised by regularly recurrent fever episodes, due to seemingly unprovoked inflammationObjectivesTo assess serum 25-hydroxy cholecalciferol...

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

BackgroundThe 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. ObjectiveTo 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 designWe 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 400IU 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. ResultsPFAPA 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). ConclusionsDeficient 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.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy syndrome is associated with activation of GM-CSF and burst-like expression of IL-8 in peripheral blood

Introduction. Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature.Methods. 23 children with PFAPA (age 6.07 ± 2.94 years, range 5–9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1–17 years) participated in the study. Peripheral blood concentrations of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology.Results. PFAPA febrile episodes were characterized by detection of GM-CSF – 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1β was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects.Discussion. PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.