Cervical Adenitis Syndrome Research Articles

PFAPA syndrome: a case report

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a complex autoinflammatory disease characterized by recurrent episodes of fever and systemic inflammatory features. It is usually a disease of children but adult onset has also been reported. The common clinical features are aphthous stomatitis, cervical lymphadenitis, pharyngitis etc with exclusion of upper respiratory tract infection and cyclic neutropenia. The patient remains completely asymptomatic between the episodes of these clinical features with normal growth and development. Here we report a case of 20-year-old male who presented with features suggestive of PFAPA syndrome and well responded with a single dose of high dose prednisolone. BIRDEM Med J 2024; 14(3): 161-165

Risk of immediate postoperative fever in PFAPA patients undergoing tonsillectomy

ObjectivePeriodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. Tonsillectomy is considered a potential treatment option.A common concept is that patients with PFAPA are more likely to have postoperative fever, which might be hard to distinguish from other etiologies such as malignant hyperthermia or drug adverse effects. For this reason, many institutions require these patients to be cared for at their main center and not at satellite centers.Our objective was to evaluate the rate of immediate postoperative fever in PFAPA patients undergoing tonsillectomy. Material and methodsFollowing IRB approval (STUDY20060029), a retrospective chart review of all PFAPA patients who underwent tonsillectomy at a tertiary children's hospital between January 1st, 2013, and September 30th, 2022.The PHIS database was queried from January 1st, 2013, to June 30th, 2022, for pediatric tonsillectomy and PFAPA. ResultsSixty-one patients underwent tonsillectomy for PFAPA during the study period at our institution. Only one (1.6 %) had immediate postoperative fever. Fever episode resolution was seen in 90.25 % of patients, 41/41 (100 %) of the patients reported fever episodes pre-op, compared with 4/41 (9.75 %) post-op (McNemar's Chi-squared test, Chi2 = 37.0, p < 0.001).481,118 pediatric tonsillectomies were recorded in the PHIS database during this period, 1197 (0.25 %) were also diagnosed with PFAPA. None of the PFAPA patients had an immediate post-operative fever. ConclusionsOur results suggest there is no increased risk of immediate postoperative fever in PFAPA patients undergoing tonsillectomy.

Exploring factors for predicting colchicine responsiveness in children with PFAPA

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) are the most common autoinflammatory syndromes in children. This study aimed to evaluate the clinical and laboratory parameters that may predict colchicine responsiveness.This retrospective, multicenter, cross-sectional study involved nine pediatric rheumatology centers from our country., The patients diagnosed with PFAPA were compared on the basis of their responses to colchicine. In the 806 (42.3% female 57.7% male) patients, the most common clinical findings were fever (100%), exudative tonsillitis (86.5%), pharyngitis (80.9%), and aphthous stomatitis (50.5%). The mean attack frequency was 13.5 ± 6.8 attacks per year lasting for a mean of 3.9 ± 1.1 days. Colchicine treatment was attempted in 519 (64.4%) patients, with 419 (80.7%) showing a favorable response. In patients who underwent MEFV gene analysis (70.8%), the most common variant was M694V heterozygous (16.8%). The presence of pharyngitis (p = 0.03, 95% CI 0.885 to 0.994), the presence of arthralgia (p = 0.04, 95% CI 0.169 to 0.958), and having more frequent attacks (p = 0.001, 95% CI 0.028 to 0.748) were found to be associated with colchicine unresponsiveness, whereas the carriage of the M694V variant (p = 0.001, 95% CI 0.065 to 0.242) was associated with colchicine responsiveness.Conclusion: This study identified the presence of pharyngitis, arthralgia, and increased attack frequency in patients with PFAPA as factors predicting colchicine unresponsiveness, whereas the carriage of the M694V variant emerged as a predictor of colchicine responsiveness. Predicting colchicine response at disease onset may facilitate a more effective management of PFAPA.What is Known:• Colchicine treatment can be used in the prophylaxis of PFAPA disease.• Having the MEFV variant is the most commonly known factor in predicting response to colchicine.What is New:• The presence of pharyngitis or arthralgia, and more frequent attacks in PFAPA disease were found to be independently associated with colchicine unresponsiveness. • Carrying the M694V variant was identified as the sole factor predicting colchicine responsiveness.

Effect of Colchicine Treatment on Clinical Course in Children with PFAPA Syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) is the most common periodic fever condition in children. There is no consensus on treatment to prevent attacks and reduce their frequency. In this study, we aimed to evaluate the effectiveness of colchicine treatment in PFAPA syndrome. In addition, we described the demographic and clinical features of PFAPA patients. We retrospectively analyzed 58 PFAPA patients who were started on colchicine treatment between January 2017 and January 2022. Demographic data, clinical features, laboratory tests, genetic analysis of MEditerranean FeVer (MEFV) mutations, and autoinflammatory disease activity index (AIDAI) scores of all patients were evaluated. In addition, patients were divided into two groups according to MEFV variants and compared. Attack frequency, duration, and AIDAI scores decreased in all patients after colchicine treatment. Duration of follow-up was 13.53±6.65 months. The median±IQR age at diagnosis was 3.2 (2-5) years. Thirty three (56.9%) patients had heterozygous mutations of MEFV. The most common MEFV variants were M694V (63.6%). There was no significant difference between the two groups in terms of colchicine responses. Colchicine treatment is effective and safe in patients with PFAPA who have frequent attacks. No association was established between the presence of heterozygous mutations of MEFV and colchicine response.

PFAPA syndróm u detí, naša skúsenosť s chirurgickou liečbou – prehľadový článok s kazuistikou

The issue of periodic fever conditions in paediatric patients is connected with wide diff erential dia gnosis. Among other causes, it is necessary to think also about the group of so-called periodic fevers syndrome, or autoinfl ammatory diseases. PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis syndrome) is the most common representative periodic fever in children’s patients. Eff ective causal treatment of this syndrome is possible within the ENT department. In the article, we provide an overview of PFAPA syndrome among autoinfl ammatory diseases and the eff ect of surgical treatment, tonsillectomy with adenotomy. Key words PFAPA syndrome – periodic fevers – Marshall syndrome – autoinfl ammatory diseases – aphthous stomatitis

Use of Streptococcus Salivarius K12 in a cohort of PFAPA patients.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) is the most common cause of periodic fever in childhood. Although PFAPA is generally a self-limited condition, it can have negative impact on child's and parents' quality of life and family functioning. Our primary aim was to assess the potential effectiveness of Streptococcus Salivarius K12 (SSK12) in preventing febrile attacks in PFAPA patients. Secondary objectives included evaluating the effectiveness of SSK12 in mitigating the severity of febrile episodes seen as a statistically significant reduction in the episode duration, highest fever temperature reached during fever, in the frequency of each associated symptom, calculated in the six months before and after the start of therapy. A total of 117 patients with PFAPA were evaluated using Marshall's criteria, modified by Thomas et al. and according to Eurofever/PRINTO classification criteria, aged 6 months to 9 years, with a median age at the onset of the disease of 2 years, treated with SSK12, since January 2021 to January 2023. Data were collected retrospectively. Before using SS K12, febrile episodes recurred on average every 26.1 ± 11.5 days, with a febrile episode duration of 4.1 ± 1.4 days. The highest fever temperature during the episode was 39.8 ± 0.7 °C. After six months of SS K12, febrile episodes recurred on average every 70 ± 53,1 days (p value <0.01), the mean lenght of febrile episodes was 3.3 ± 1.6 (p value <0.01) and the highest fever temperature reached during the febrile episode was 39.1 ± 1.1 °C (p value <0.01). We also documented a reduction in the frequency of exudative pharyngotonsillitis present in 72 vs. 103 patients (p value <0.01), oral aphthosis present in 47 vs. 80 patients (p value <0.01), lateral cervical lymphadenopathy in 45 vs. 83 (p value <0.01). Erythematous pharyngotonsillitis decreased in frequency but it was not statistically significant. The results of our study indicate that the use of SS K12 could be beneficial in decreasing febrile episodes related to PFAPA syndrome and its associated symptoms, potentially improving the quality of life in pediatric patients and decreasing the need for additional pharmacological therapies.

Periyodik Ateş Aftöz Stomatit Farenjit Servikal Adenit Sendromlu Çocuklarda Kolşisin Yanıtının Belirleyicileri

Colchicine prophylaxis is one of the treatment options in management of patients with periodic fever aphthous stomatitis pharyngitis and cervical adenitis (PFAPA) syndrome, but variability exists in response to the treatment. Here we aimed to investigate the efficacy of colchicine prophylaxis and factors associated with a favorable response. Patients diagnosed with PFAPA in whom colchicine was employed before 5 years old age were included. Response to the prophylaxis was assessed by the change of fever intervals and an increase of fever interval &amp;gt;50% after treatment was accepted as favorable response. Complete response was defined as a fever free interval of &amp;gt; 3 months in patients displayed favorable response. Among 41 patients, a favorable response, was observed in 20 (48.8%) patients, and among favorable responders, 8 (19.5%) patients displayed complete response. Of the remaining patients without a favorable response, 9 (22%) demonstrated no response to colchicine prophylaxis. Despite colchicine response was not associated with clinical and laboratory features including MEFV mutations and previous corticosteroid usage, shorter fever intervals were found to be significantly increased the odds of a favorable response to colchicine, which might aid in therapeutic decisions in management of patients with PFAPA.

Extreme Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA): a discrete group of patients

ObjectivePeriodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA).Study design: The medical records of 365 patients with PFAPA who attended Schneider Children’s Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson’s chi-squared, and Fisher’s exact tests.ResultsForty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7–2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment.ConclusionAbout half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.

Variables fordifferential diagnosis offamilial Mediterranean fever: Multiple correspondence analysis ofa large Japanese cohort.

We investigated differential diagnoses that should be noted with familial Mediterranean fever (FMF) and useful variables for differentiation in a large Japanese cohort. Patients aged ≥13 years who were clinically suspected of having FMF by Livneh criteria were studied 1 year after MEFV genetic testing. Patients ultimately diagnosed with other diseases were studied, and the association among each disease, patient characteristics, and clinical variables were analysed using multiple correspondence analysis. In total, 504 patients were included in this study; 34 (6.7%) were diagnosed with a disease other than FMF. The most common diagnosis was Behçet's disease, followed by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, inflammatory bowel disease, myelodysplastic syndromes (MDS), and infectious diseases. Although none of the non-FMF patients had exon 10 variants, some responded to colchicine treatment. Multiple correspondence analysis suggested that atypical symptoms such as stomatitis were associated with Behçet's disease and PFAPA syndrome, whereas characteristic situations such as disease onset ≥40 years were associated with MDS and infectious diseases. Careful follow-ups and reanalysis of the diagnosis should be performed for patients with atypical findings and no exon 10 variants, even if their symptoms meet the clinical criteria for FMF.

Tonsillectomy reduces the family impact of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and improves health-related quality of life in affected children

BackgroundPeriodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disorder that primarily affects young children, and typically gives rise to fever episodes that recur monthly for several years. This study investigated the impact of PFAPA syndrome on the families of affected children, the health-related quality of life (HRQOL) of children with the syndrome, and how these factors were influenced by tonsillectomy.MethodsThis prospective cohort study included 24 children with typical PFAPA syndrome that were referred for tonsillectomy, of whom 20 underwent the procedure. The control group consisted of randomly selected children from the general population. Family impact and HRQOL were measured using the standardized, validated questionnaires Pediatric Quality of Life Inventory™ (PedsQL™) Family Impact Module (FIM) and PedsQL™ 4.0 Generic Core Scales (GCS). Parents to children with PFAPA completed the questionnaires before and 6 months after their child underwent tonsillectomy, and HRQOL was measured both between and during PFAPA episodes. The Wilcoxon signed-rank test was used to compare data before and after tonsillectomy in the patient group, while the Mann–Whitney test was used for comparison of the patient and control groups.ResultsBefore tonsillectomy, children with PFAPA had significantly lower scores than the control group on the PedsQL™ FIM and the PedsQL™ 4.0 GCS during fever episodes. After tonsillectomy, all patients improved with diminished febrile episodes, which resulted in significantly higher scores regarding both family impact and HRQOL at the time of follow-up. HRQOL of in children with PFAPA improved after tonsillectomy even when compared to afebrile intervals before the procedure. The differences between PFAPA patients and controls were eliminated after tonsillectomy.ConclusionPFAPA syndrome has a profound negative impact on the families of affected children. Tonsillectomy that leads to cessation or reduction of fever episodes eases the impact of the disease on the family. HRQOL in children with PFAPA is low during febrile episodes and similar to healthy controls in between episodes. The improvement of HRQOL in patients with PFAPA after tonsillectomy compared to the afebrile intervals before tonsillectomy highlights that the constantly recurring fevers may affect the children’s well-being even between fever episodes.

Preliminary data revealing efficacy of Streptococcus salivarius K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

To evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12. SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Can the effectiveness of tonsillectomy for PFAPA syndrome be predicted based on clinical factors.

To evaluate the clinical factors associated with the outcome of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, thereby clarifying who would most likely benefit from that surgery. This was a case-control study of 53 PFAPA patients who underwent tonsillectomy and were divided into a complete-resolution group and a postoperative-fever group. Logistic regression analyses were performed using 17 clinical factors as variables to identify factors associated with the surgical outcome. Hierarchical cluster analysis was also performed to evaluate for relationships between phenotypes and surgical outcomes. Thirty-nine (73.6%) patients had complete resolution after tonsillectomy. In simple logistic regression analysis, the surgical outcome showed significant positive trends with late-onset (odds ratio [OR] 7.1, P=0.02) and presence of headache (OR 6.5, P=0.01). In stepwise multiple logistic regression analysis adjusted for age at onset, presence of headache was significantly associated with complete resolution (OR 6.5, P=0.01). The complete resolution rates for each combination of headache status and age at onset were as follows: presence of headache/age at onset ≥36 months, 100% (14/14); presence of headache/age at onset <36 months, 76.9% (10/13); absence of headache/age at onset ≥36 months, 75.0% (6/8); and absence of headache/age at onset <36 months, 43.8% (7/16). In hierarchical cluster analysis, complete resolution, age at onset, and headache were in the same cluster. PFAPA patients with headache and late onset responded well to tonsillectomy. The mechanisms underlying this association may warrant further investigation.

Evaluation of common NLRP3 Q703K variant in pediatric patients with autoinflammatory disease: CAPS and PFAPA.

Gain-of-function mutations of the NLR family pyrin domain containing 3 (NLRP3) gene have been implicated in autoinflammatory diseases. The NLRP3 Q703K variant is a common variant associated with Cryopyrin-associated periodic syndromes (CAPS) and periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, the genotype-phenotype correlation between NLRP3 Q703K variant, CAPS and PFAPA is unclear. In this study, we aimed to investigate the frequency of the NLRP3 Q703K variant in patients with and without autoinflammatory disease and characterize the phenotype in only Q703K variant positive patients. A retrospective analysis of 639 patients with autoinflammatory symptoms was conducted. Patients underwent next-generation sequencing (NGS) panel analysis of 16 genes, including NLRP3. For the 68 patients carrying the only Q703K variant, their clinical and demographic information was evaluated. Genetic data from 1461 patients without autoinflammatory symptoms were used as the control group. Of our 639 autoinflammatory symptomatic patients, the Q703K mutation was detected in 68 (5.3% allele frequency). Heterozygous mutations were detected in 141 patients without autoinflammatory symptoms (4.8% allele frequency, p=0.4887). Of the patients with variant in Q703K, 10 patients were diagnosed with CAPS , 7 patients were diagnosed with PFAPA and the remaining 39 were diagnosed with undefined systemic autoinflammatory disease (uSAID) Conclusions. The Q703K variant, which is seen with similar frequency in the control and autoinflammatory groups, is also of higher prevalence in patients with mild CAPS symptoms and PFAPA syndrome. This variant, together with other undetected genetic variants or epigenetic modifications, may be responsible for the corresponding phenotype. As such, it is essential for clinicians to evaluate their patients using both genetic and clinical evaluations.

Epidemiology and clinical features of PFAPA: a retrospective cohort study of 336 patients in western Sweden

BackgroundPeriodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is generally regarded as the most common autoinflammatory disease, but the epidemiology of the disease is largely unknown. The objectives of this study were to estimate the annual incidence and describe the clinical features of PFAPA in a large cohort from western Sweden.MethodsThe study retrospectively included children < 18 years of age diagnosed with PFAPA between 2006 and 2017 at three hospitals: NU Hospital Group, Skaraborg Hospital and Queen Silvia Children’s Hospital. Patients were identified by searching for relevant diagnostic ICD-10 codes in the comprehensive electronic medical records and data were retrieved by reviewing case records. To estimate incidence, patients with symptom onset from January 1, 2006, to December 31, 2016, were included. Population data for the study area during this period were retrieved from Statistics Sweden.ResultsIn this study, 336 patients with PFAPA were identified. Of these, 156 (46%) were girls and 180 (54%) were boys. Almost 90% of the children with PFAPA (291 patients) experienced their first symptoms before the age of 5 years and fewer than 3% presented at ages above 10 years. Pharyngitis was the most common symptom during febrile episodes, followed by cervical adenitis and aphthous stomatitis. Fourteen percent of the patients displayed atypical features, of which skin rash was the most common.To calculate incidence, 251 patients with symptom onset during the study period were identified. The mean annual incidence was estimated at 0.86/10,000 for children < 18 years of age and 2.6/10,000 for children < 5 years of age.ConclusionsThis study adds to the understanding of the epidemiology of PFAPA syndrome by presenting incidence rates based on a large cohort and in different age groups in a population-based setting. It also shows the distribution of age of onset of PFAPA, with a peak in 1-year-olds and waning at older ages. Signs and symptoms of PFAPA syndrome were similar in children with symptom onset before vs. after 5 years of age.

NLRP3 gene variants and serum NLRP3 levels in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome.

Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points • Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. • Elevated serum or plasma levels of IL-1β, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. • It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.

Colchicine versus cimetidine: the better choice for Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome prophylaxis, and the role of MEFV gene mutations

BackgroundDuring childhood, the most common periodic fever is periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The effective treatment and prevention of febrile attacks improve these patients' and their families’ quality of life. However, there is no single strategy or evidence-based guideline to manage this syndrome, and most of them are based on consensus treatment plans.MethodsThis randomized controlled trial was carried out on 67 PFAPA patients referred to three tertiary centers of pediatric rheumatology. The patients were divided into two groups, including group 1 (n = 36) receiving prednisolone plus colchicine and group 2 (n = 31) receiving prednisolone plus cimetidine. Demographic characteristics and the number of febrile episodes were compared between the two groups before and after the intervention.ResultsIn both groups, the number of febrile episodes after the treatment decreased (P ≤ 0.001). Statistical Analysis showed no significant difference between the two groups (P = 0.88). Moreover, 44 patients from both groups were checked for the MEFV gene. There were no statistical differences between MEFV positive and negative subgroups in response to colchicine (P = 1).ConclusionThis study showed that both drug regimens are significantly effective in preventing febrile attacks in PFAPA syndrome, and the presence of a MEFV gene mutation might not be the only significant risk factor for a response to colchicine.Trial registrationIRCT, IRCT20191222045847N1. Registered 23 October 2019, https://fa.irct.ir/search/result?query=IRCT20191222045847N1

PFAPA syndrome: A practical review

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is rare, benign recurrent/periodic fever syndrome of unknown etiology that normally affects children under the age of 5. The diagnosis is made based on clinical assumption, after excluding other pathology. In this report to provide a practical assessment of PFAPA syndrome regarding epidemiology, pathogenesis, natural history, clinical manifestations, diagnosis criteria, differential diagnosis, and available medical and surgical treatments.

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome.

ObjectiveAim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome.MethodsThis is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries.ResultsA total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems.ConclusionsThe development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on https://clinicaltrials.gov NCT 05200715.

Increased Frequency of Febrile Seizures in Two Periodic Fever Syndromes: Familial Mediterranean Fever and PFAPA Syndrome.

Objective:Our aim in this study is to reveal the frequency of febrile seizures in patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome and to compare it to normal population.Materials and Methods:Patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome, who were diagnosed according to Turkish pediatric Familial Mediterranean Fever diagnostic criteria and Marshall criteria, were enrolled to the study. A form containing questions about febrile seizures history was prepared for Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome patients. Demographic data and febrile seizures history of Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis patients were obtained by calling the parents by phone. Familial Mediterranean Fever patients were randomly selected during their routine follow-up. The frequency of febrile seizures in both disease groups was compared with the prevalence of previous febrile seizures studies in the general population in Turkey.Results:A total of 417 Familial Mediterranean Fever and 152 Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis subjects were recruited to the study. The frequency of febrile seizures in Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome was similar (8.4% vs. 8.6%; P > .05). The frequency of febrile seizures in Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome patients was found to be significantly higher than the frequency in general population (8.4% vs. 4.4%) [P < .0001, OR: 1.99 (CI: 1.4-2.8)]; (8.6% vs. 4.4%) [P < .01, OR: 2.03 (CI: 1.1-3.6)], respectively.Conclusion:The frequency of febrile seizures in patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome was found to be significantly higher than in the general population. This increased frequency of febrile seizures in both periodic syndromes seems to be a result of recurrent fever.

The role of inflammatory mediators in the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome.

As a recurrent disease, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is characterized by episodes of febrile attacks and is often prominent in children under five years of age. However, the etiology of this condition has not been fully understood yet. The search in the extensive literature of peer-reviewed articles published from the inception to December 2021 was conducted to identify the relevant studies, using the electronic databases of MEDLINE/PubMed, Embase, Scopus, the Cochrane Library, and the Web of Science. The analysis of complex relationships indicates that inflammatory factors, such as various cytokines and acute-phase proteins (APPs), play leading roles in the pathogenesis of this disease. Accordingly, this article summarizes the current state of knowledge to explain the mechanisms involved in inflammatory responses among patients with PFAPA syndrome and investigate its role in the pathogenesis of this disease. Moreover, the possibilities for further implementation of new therapeutic strategies are pointed out. It is concluded that some pathophysiological processes are associated with immune dysregulation, which itself may be secondary to environmental factors, genetic background, and underlying diseases, including latent infections that multiply inflammatory mediators. elevated inflammatory markers similarly play a significant part in the clinical outcomes of this condition, whose pyrogenic nature is the reason for the development of episodes of febrile attacks in the population of patients suffering from PFAPA syndrome.