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.

Risk of immediate postoperative fever in PFAPA patients undergoing tonsillectomy.

OBJECTIVE: Periodic 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 METHODS: Following 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. RESULTS: Sixty-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. CONCLUSIONS: Our results suggest there is no increased risk of immediate postoperative fever in PFAPA patients undergoing tonsillectomy.

Does having MEFV gene sequence variants affect the clinical course and colchicine response in children with PFAPA syndrome?

The primary aim of this study was to document the treatment modalities used in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and look for the efficacy and safety of colchicine in the treatment of PFAPA patients. The secondary aim was to search for whether having MEFV (Mediterranean fever) gene sequence variants affect the clinical course and response to colchicine. The study was conducted in 2 pediatric rheumatology centers. The patients that have been diagnosed with PFAPA syndrome between December 2017 and December 2021 were evaluated retrospectively. The study included 157 patients with PFAPA syndrome (54.8% boys and 45.2% girls). The median follow-up duration was 18 (IQR: 12-30) months. One hundred and fifty-five patients (98.7%) had exudative pharyngitis, 120 patients (76.4%) had aphthous stomatitis, and 82 patients (52.2%) had cervical lymphadenitis during the attacks. Clinical features during attacks were not affected by the presence or absence of the MEFV gene sequence variants. Corticosteroid treatment during attacks was given to 152 patients (96.8%). The frequency of fever attacks did not change in 57 patients (37.5%), increased in 57 patients (37.5%), and decreased in 38 patients (25%) after corticosteroid use. Colchicine was given to 122 patients (77.7%) in the cohort. After colchicine treatment, complete/near-complete resolution of the attacks was observed in 57 patients (46.7%). Colchicine led to partial resolution of the attacks in 59 patients (48.4%). In only 6 patients (4.9%), no change was observed in the nature of the attacks with colchicine treatment. The median duration of the attacks was 4 (IQR: 4-5) days before colchicine treatment, and it was 2 (IQR: 1-2.5) days after colchicine treatment. Also, a significant decrease in the frequency of the attacks was observed before and after colchicine treatment [every 4 (IQR: 3-4) weeks versus every 10 (IQR: 8-24) weeks, respectively, (p < 0.001)]. The overall response to colchicine was not affected by MEFV sequence variants. It was seen that the frequency of fever attacks decreased dramatically in both groups, and children with MEFV variants had significantly less attacks than children without MEFV variants after colchicine treatment (every 11 weeks vs every 9.5 weeks, respectively, p: 0.02). CONCLUSION: Colchicine seems to be an effective and safe treatment modality in PFAPA treatment. It led to a change in the nature of the attacks either in the frequency, duration, or severity of the attacks in 95.1% of the patients. This study has shown that having MEFV gene sequence variants did not affect the clinical course or response to colchicine. We recommend that colchicine should be considered in all PFAPA patients to see the response of the patient, irrespective of the MEFV gene mutations. WHAT IS KNOWN: • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever syndrome in the world. Familial Mediterranean fever (FMF) is the most common cause of periodic fever syndrome in Turkey. • Colchicine has become a new treatment option in PFAPA. WHAT IS NEW: • Some PFAPA patients have Mediterranean fever (MEFV) gene variants, and it is speculated that PFAPA patients with MEFV gene mutations respond better to colchicine. • The aim of this study was to look for this hypothesis. We have seen that the clinical phenotype and colchicine response of PFAPA patients were not affected by MEFV gene sequence variants.

Gray zone in the spectrum of autoinflammatory diseases: familial Mediterranean fever accompanying periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: single-center experience.

Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1-77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7-90) days. The median disease duration was 46 (6-128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine.     Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness. What is Known: • A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria. • While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients. What is New: • In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance. • The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment.

Long-term efficacy of tonsillectomy/adenotonsillectomy in patients with periodic fever aphthous stomatitis pharyngitis adenitis syndrome with special emphasis on co-existence of familial Mediterranean fever.

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is one of the most common autoinflammatory fever disorders in the childhood which may co-exists with familial Mediterranean fever (FMF) causing treatment complexity. As the role of surgery in PFAPA syndrome is still controversial, in this paper, our aim is to present our results of tonsillectomy/adenotonsillectomy in the treatment of PFAPA syndrome. Archives of a tertiary care hospital were investigated for patients who underwent tonsillectomy or adenotonsillectomy due to PFAPA Syndrome between 2010 and 2020. 344 patients were found but only 281 of them were accessible. Through phone call interview and chart review methods, preoperative and postoperative the number and severity of the attacks and general satisfaction after the operation were recorded and analyzed. Also, patients with concomitant FMF were analyzed separately. A total of 281 patients were included in the study. There was no improvement in 10 (3.55%) patients. Eight (2.84%) patients showed mild improvement, 29 (10.32%) patients had moderate improvement and 234 (83.27%) patients had full recovery after tonsillectomy. There were 266 PFAPA patients without FMF. No improvement, mild improvement, moderate improvement, and full recovery in this patient group were 5 (1.9%), 6 (2.3%), 25 (9.4%) and 230 (86.5%), respectively. FMF was present in 5.33% (15/281) of the patients. In PFAPA + FMF group 5 patients had no improvement (33.3%), 2 had mild improvement (13.3%), 4 had moderate improvement (26.7%) and 4 had full recovery (26.7%). Benefit of tonsillectomy was significantly lower in the patients with concomitant FMF when compared to the patients who did not have FMF (p < 0.001). Age of diagnosis, age of operation, severity of the disease, type of operation, and gender were found to have no significant relationship with the benefit from surgery (p < 0.05). According to the findings of this study, tonsillectomy is an effective long-term treatment for PFAPA syndrome with success rate of 83.27%. Also, preoperatively FMF should be considered in these patients, which dramatically reduces surgical efficacy.

Diagnostic performance of routine blood parameters in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

BACKGROUND: We aimed to investigate the difference between PFAPA and streptococcal tonsillitis (Strep Pharyngitis) by using blood parameters. We want to evaluate the relationship between periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, and tonsillitis by using NLR. METHODS: The data of 141 pediatric patients who had applied to our clinic between October 2016 and March 2019 and were diagnosed with PFAPA syndrome and tonsillitis were reviewed from hospital records. The demographic data of the study group were recorded, as were their WBC, neutrophil, and lymphocyte counts, NLR, and MPV values, which are obtained by proportioning these two counts. RESULTS: CRP and ESR values were significantly higher in the PFAPA group (p = 0.026 and p < 0.001, respectively). No significant difference was determined between the groups in terms of platelet count or lymphocyte count. Receiver operating curve analyses were calculated. The AUC was 0.713 ± 0.04 according to age, and the CRP was 0.607 ± 0.04 (95% confidence interval). Using a cutoff point of >49 months for age, the sensitivity was 0.71 and the specificity was 0.67. CONCLUSION: With simple laboratory parameters, PFAPA syndrome can be differentiated from a diagnosis of tonsillitis. This may reduce the costs associated with unnecessary antibiotic use. However, these findings still need to be confirmed by other future studies.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

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

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Probiotic use in the prophylaxis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a retrospective cohort study.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is an autoinflammatory recurrent fever syndrome that mainly affects children. Probiotics are currently used to prevent upper respiratory tract infections and flares of diseases associated with immune dysregulation. We aimed to evaluate the response to probiotic treatment in PFAPA patients. Patients with PFAPA syndrome who received probiotics and were followed between July 2019 and July 2021 were included in this retrospective study. Demographic and clinical features and response to probiotics were assessed. Twenty out of 111 children with PFAPA syndrome (F/M:1) were included. The median (min-max) ages at symptoms onset and diagnosis were 24 (3-72) and 51.5 (11-120) months, respectively. All 20 patients received probiotics during the disease course. The probiotic preparation they received included a combination of two lactobacilli as Lactobacillus plantarum HEAL9 (Lp HEAL9) and Lactobacillus paracasei 8700:2 (Lpa 8700:2). The median age at probiotic onset was 60 (33-192) months, while the duration of probiotic use was 4.5 (3-19) months. All patients except one experienced a decrease in attack frequency with probiotic use. After probiotic treatment, the median number of episodes during 3 months decreased from 3 to 1 (p < 0.001). Eight (40%) patients had no attacks during the 3 months after probiotic initiation. And, 5 (45%) of 11 patients who had ≥ 1 attacks on probiotics mentioned that the attack severity decreased significantly after probiotic initiation. Our results suggest that probiotic strains Lactobacillus plantarum HEAL9 and Lactobacillus paracasei 8700:2 could be beneficial in PFAPA patients by decreasing the attack frequency.

Galectin-3: a new biomarker for differentiating periodic fever, adenitis, pharyngitis, aphthous stomatitis (PFAPA) syndrome from familial Mediterranean fever?

Differentiating PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome from familial Mediterranean fever (FMF) could be challenging in some cases. Galectin-3 is a lectin with regulatory functions in apoptosis and inflammation. We aimed to test whether galectin-3 could be a biomarker for differentiating PFAPA syndrome from FMF. Patients with PFAPA syndrome, FMF, cryopyrin-associated periodic syndrome (CAPS), and streptococcal pharyngitis, and healthy controls were included in this study. Serum galectin-3 levels were measured using enzyme-linked immunosorbent assay. Eighty-seven patients (36 with PFAPA, 39 with FMF, 8 with CAPS, 4 with streptococcal pharyngitis), and 17 healthy controls were included. Blood samples were drawn during attacks from 20 PFAPA and 7 FMF patients and attack-free periods from 22 PFAPA, 35 FMF, and 8 CAPS patients. The median serum galectin-3 level in the PFAPA-attack group (1.025 ng/ml) was significantly lower than the levels in healthy control (2.367 ng/ml), streptococcal pharyngitis (3.021 ng/ml), FMF attack (2.402 ng/ml), and FMF-attack-free groups (2.797 ng/ml) (p = 0.006, 0.03, 0.01, and < 0.001, respectively). PFAPA-attack-free group had lower galectin-3 levels than the FMF-attack-free group (1.794 vs. 2.797 ng/ml, respectively; p = 0.01). Galectin-3 levels did not differ significantly between CAPS and attack-free PFAPA patients (1.439 ng/ml vs. 1.794 ng/ml, respectively; p = 0.63). In our study, for the first time, we defined galectin-3 as a promising biomarker that differs between PFAPA and FMF patients during both disease flares and attack-free periods. Further studies with high number of patients could validate its role as a biomarker.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) or recurrent urinary tract infections: a case report.

BACKGROUND: Fever is the most frequent reason for medical consultation in children, and makes up 15-25% of all consultations in primary care and emergency departments. In here we report a case of a 13 year-old girl who referred with an unusual presentation of fever and was misdiagnosed with recurrent urinary tract infection for 8 years. CASE PRESENTATION: This is a Clinical Reasoning Cycle case study. A 13 year-old girl was referred with a chief complaint of recurrent fevers from 8 years. During her first febrile episode, she had a 5-day high-grade fever associated with loss of appetite. Her physical examination at that time was unremarkable. Blood tests showed leukocytosis with a shift to the left and urine examination was in favor of pyuria. The urine culture was positive for bacterial growth. The episodes of fever were repeated every 45 days. Accordingly, the patient was diagnosed as a case of recurrent urinary tract infection. In the intervals between her febrile episodes, the patient was healthy and laboratory tests were normal. Ultrasonography, voiding cystourethrogram and dimercaptosuccinic acid scans were normal. During her last visit, the patient mentioned difficulty in swallowing and on examination cervical lymph nodes, exudative tonsillitis and painful aphthous stomatitis were detected. All antibiotics were stopped and corticosteroids were started. The patient's symptoms were relieved and the interval between her febrile episodes became longer. CONCLUSIONS: Our study shows that a patient should never be marked, particularly when the symptom and signs aren't completely justifying a patient's condition.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome: Clinical characteristics and treatment outcomes - a single center study in Japan.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease occurring in children. Although PFAPA is the most common periodic fever syndrome found in children, there are only a few studies defining the clinical characteristics and the efficacy of treatment strategies among Japanese children. This study aimed to clarify the demographic characteristics and clinical features of patients with PFAPA syndrome and to evaluate treatment efficacy. METHODS: We retrospectively reviewed the clinical features of children with PFAPA who visited Saitama Children's Medical Center between January and December 2019. We also evaluated treatment strategies and their efficacy; abortive treatment with corticosteroids, prophylaxis with cimetidine or colchicine, and surgical management with tonsillectomy. RESULTS: A total of 100 Japanese children (61% male) with PFAPA were included. Median age of onset was 3 years, median duration of fever episodes was 5 days, and median interval between episodes was 4 weeks. The symptoms (frequencies) were pharyngitis (89%), exudate on tonsils (71%), cervical adenitis (50%), and aphthous stomatitis (49%). Approximately 37% of patients took prednisolone for aborting fever attacks, showing a 100% response; 93% were treated with cimetidine, showing an 79.6% response, and 18% were treated with colchicine, showing a 66.7% response. Only one patient underwent tonsillectomy. CONCLUSIONS: Among Japanese children with PFAPA, 28% of them were ≥5 years with a male predominance. Pharyngitis is the most frequent symptom associated with fever. Cimetidine is suitable for initial therapy because of its safety and efficacy.

[Autoinflammation-differences between children and adults]. / Autoinflammation ­ Unterschiede bei Kindern und Erwachsenen.

Autoinflammatory diseases present as multisystemic inflammation and often manifest in early childhood. In contrast, in a few diseases, e.g., the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome, the first symptoms occur exclusively in adulthood. This article describes how the phenotypic expression and severity of individual autoinflammatory diseases differ depending on age. Furthermore, differences in the development of organ damage in children and adults are pointed out. In addition to the hereditary periodic fever syndromes, the clinical picture of deficiency of adenosine deaminase 2, the interferonopathies, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome as well as VEXAS and Schnitzler syndromes are highlighted.

The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

This study was conducted to investigate the relationship between clinic features and Mediterranean fever gene (MEFV) variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. In total, 167 patients with PFAPA syndrome were included in the study. Female:male ratio of the patients was 0.75 (72 females, 95 males). In total 59.9% of patients with PFAPA had at least one MEFV variant and the most common heterozygous variants were M694V in 29.3% of the patients (40/167), E148Q in 8.3% (14/167), and V726A in 7.1% (12/167). The median age at the disease onset was significantly higher and the median duration of the episodes was significantly lower in patient with variants in exon 10 comparing to the others (both p = 0.01). Similarly, the median age at the disease onset was significantly higher (p = 0.01) and the median duration of the episodes was significantly lower (p = 0.04) in patient with MEFV variants than in the remaining patients. There were no significant differences according to the genotypes of the patients in terms of both treatment response and the frequency of clinical findings.Conclusion: In PFAPA syndrome, MEFV variants may be a modifier for disease onset and attack duration. What is Known: • Due to periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome having clinical findings resembling familial Mediterranean fever (FMF), it can be difficult to distinguish PFAPA syndrome and FMF especially in endemic regions for FMF. • Underlying MEFV mutations could affect the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome's clinical presentation and response to treatment. What is New: • Having one of the underlying MEFV variants is related to later disease onset and shorter episode duration in patients with PFAPA syndrome.

IL-1ß blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and familial Mediterranean fever (FMF) are considered as inflammasome disorders associated with uncontrolled interleukin (IL)-1ß production. Anti-IL1 agents are used in colchicine-resistant cases of FMF. Increase in pro-inflammatory mediators even between febrile attacks in PFAPA suggests that anti-IL1 treatment might be beneficial in these patients. We describe a child presenting with recurrent, self-limited febrile attacks at 1 year of age who was diagnosed as FMF being heterozygous for M694 V mutation. Her clinical findings were only controlled by the addition of canakinumab (2 mg/kg/8 week) to colchicine treatment. However, she developed typical PFAPA attacks during this treatment at 3 years of age. We conducted a literature search focusing on English articles with keywords including PFAPA, anakinra, canakinumab, and rilonacept. Five children and one adult patient with PFAPA were found and evaluated. Anakinra was reported to abort PFAPA attacks in children, while the adult patient first responded and then became resistant to anakinra. Canakinumab was effective in preventing febrile attacks in this patient. Failure of canakinumab to prevent PFAPA attacks in our case may arise from the differences in the pathophysiology of PFAPA and FMF. Thus, further experience with higher doses or shorter intervals of canakinumab is needed in children with PFAPA.

Vestibular involvement of PFAPA syndrome.

OBJECTIVE: PFAPA syndrome is derived from the initials of the English words of the findings that make up the syndrome ("Periodic Fever", "Aphthous Stomatitis", "Pharyngitis", "Adenitis"). This study aims to evaluate the vestibular system in patients with PFAPA syndrome by the cVEMP test and to give a general review of PFAPA syndrome in light of current literature. METHODS: In this prospective study, 30 patients aged 4-6 who were diagnosed with PFAPA in a tertiary pediatrics clinic, between January 2016 and February 2020 and 30 children of the same age group who applied to a tertiary otorhinolaryngology clinic for other reasons and proven to have no hearing or vestibular problems were included and in addition to routine physical examination, electromyographic activity of the sternocleidomastoid muscle surface was measured. RESULTS: We found that the amplitude difference between cVEMP p1-n1 in patients with PFAPA syndrome in both ears decreased compared to the healthy control group. CONCLUSION: Our study proves there is a vestibular system involvement of PFAPA syndrome. This study is the first in the literature to search the relationship between PFAPA and the vestibular system.

Clinical Usefulness of Acute-Phase Markers in Distinguishing between PFAPA and Other Exudative Tonsillitis Causes: A Methodological Study.

BACKGROUND: We investigated the practical use of procalcitonin (PCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and complete blood count (CBC) parameters in distinguishing periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) attacks from exudative tonsillitis associated with group A streptococcus (GAS) and Epstein-Barre virus (EBV). METHODS: The study population consisted of cases with exudative tonsillitis who had been subsequently diagnosed as PFAPA, EBV, and GAS tonsillitis through a period of 6 years. We retrieved the CBC, ESR, CRP and PCT data from patients' medical records. RESULTS: Of the patients, 47 (35.6%) had PFAPA, 36 (27.3%) had GAS and 49 (37.1%) had EBV tonsillitis. Median CRP, ESR and PCT values of patients with PFAPA were 78 (17-92) mg/dl, 44 (11-83) mm/h, 0.16 (0.01-1.45) ng/ml, respectively. The CRP and ESR levels were significantly higher in PFAPA and GAS groups compared with the EBV group (p = 0.001). There was no significant difference between the groups regarding the PCT levels. CONCLUSION: The study indicated no benefit of PCT in distinguishing PFAPA from the others. However, we found that CRP, ESR, and CBC parameters could be useful in identifying PFAPA and GAS than EBV tonsillitis.

Performance of recently proposed periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria in a region endemic for familial Mediterranean fever.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

The MEFV gene and its association with familial Mediterranean fever, severe atopy, and recurrent respiratory tract infections.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease and is characterized by self-limiting episodes of fever and polyserositis. The aim of this study was to determine the atopic clinical findings associated with the MEFV gene. METHODS: A retrospective chart review was conducted of pediatric patients who had received a diagnosis of familial Mediterranean fever between August 2015 and November 2018. RESULTS: A total of 454 patients with familial Mediterranean fever were evaluated. The median age of diagnosis was 60 months (min-max: 6-228) and the percentage of patients who were male was 57.5%. A MEFV gene mutation was determined in 310 (68.3%) children. The most frequent genetic mutation was a R202Q heterozygote mutation, which was found in 95 patients (20.9%). When compared with MEFV-negative patients, elevation of serum amyloid A and fibrinogen levels during an episode of FMF was found to occur more frequently in MEFV-positive patients (p=0.019 and 0.027, respectively). Male gender, cigarette exposure, and a younger diagnosis age were seen more frequently in patients who had episodes with fever (p=0.039, 0.022, and 0.001, respectively). Chronic cough with sputum and persistent purulent rhinitis were more frequent in the group which did not experience fever episodes (p=0.003 and 0.002, respectively). CONCLUSIONS: While being a periodic fever syndrome, familial Mediterranean fever also presents as a multisystemic disease with heterogeneous clinical symptoms. Severe atopic diseases and recurrent respiratory tract infections are characteristic features of this disease.

Long-term management of patients with PFAPA syndrome.

OBJECTIVE: To evaluate the long-term treatment results of patients with PFAPA syndrome and to determine their need for tonsillectomy. MATERIALS AND METHODS: The clinical characteristics, treatments and long-term results of 16 patients admitted to the Pediatric and Otorhinolaryngology Clinic between 2015 and 2019 were retrospectively analyzed. RESULTS: Twelve male and four female patients were examined between 1.5 and 8 years (mean age 4.8 ± 1.1) (75% male, 25% female). The mean duration of attacks was 4.4 ± 1.4 weeks. Twelve patients recovered completely with single-dose steroid therapy. In the 4-year follow-up of 12 patients who were given a single dose of steroid therapy, there were no relapses. Surgical decisions were made for four patients whose attacks did not pass with steroid treatment. Two patients (75%) underwent adenotonsillectomy, and one patient underwent tonsillectomy While three of these patients did not have an attack again, one patient continued to have an attack every 8 weeks. At the age of 9, his attacks were completely resolved spontaneously. All patients had fever. The most common concomitant symptoms were pharyngitis (94%), cervical adenitis (82%) and aphthous stomatitis (77%). Exudative tonsillitis was present in 25% of the patients. CONCLUSION: Medical treatment should be the first treatment option in patients with PFAPA syndrome. Although single-dose steroid treatment is effective in these patients, tonsillectomy is an important treatment option in refractory cases.