Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis Research Articles

Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation

BackgroundSystemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries.MethodsData of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients.ResultsClinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria.ConclusionsPatients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

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

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. 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. 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. 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.

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.

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 flares observed during COVID outbreak: can emotional stress trigger PFAPA attacks? A multicenter cohort study

ObjectiveIt is common knowledge among clinicians who treat PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) patients that emotional stress can trigger PFAPA attacks similarly to other autoinflammatory diseases. However, it has never been proved scientifically. Our aim was to examine whether emotional stress serves as a trigger for PFAPA attacks.MethodsPatients aged 3-12 years, with active PFAPA, from two Israeli medical centers were enrolled to this study. Patient's parents were reached via phone calls in two occasions: a stressful period related to the COVID-19 pandemic restrictions and a less stressful period. In both times they were asked to report occurrence of PFAPA attacks in the preceding 2 weeks. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. The significance level was set at 0.05.ResultsMean age was 7.28 ± 2.7 for the 99 paediatric patients enrolled in the study. Scores for the mean emotional distress questionnaire were statistically significant higher in the stressful period compared to the less stressful period (35.6 ± 8.1 vs. 32.1 ±7.7, respectively, P = 0.047). In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the less stressful period (p = 0.017).ConclusionPFAPA flares during COVID-19 outbreak are described. This study is the first to suggest that emotional stress is associated with PFAPA attacks.

Clinical characterization, long-term follow-up, and response to treatment of patients with syndrome of undifferentiated recurrent fever (SURF)

ObjectivesTo describe a homogeneous group of patients with undifferentiated recurrent fevers followed-up in a tertiary referral center for systemic autoinflammatory diseases (SAIDs). MethodsPatients with undifferentiated recurrent fevers seen at our Center from 2008 to 2021 and followed-up for at least one year were included in a retrospective study. Monogenic recurrent fevers, patients carrying variants of unknown origin and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome were excluded. ResultsFifty patients (34 male, 16 female) were included in the study. The median age at onset was 3 years, and the median follow-up was 3.3 years. At baseline, arthralgia (70%) and abdominal pain (65%) were the most frequent manifestations. NSAIDs or steroids on demand had a variable and transient effect. Tonsillectomy was ineffective in the 10 patients (20%) that underwent surgery. Forty-eight patients (96%) were treated with colchicine. A complete response (absence of fever) was achieved in 31 patients (64.6%). Nine patients (18%) showed a partial response, with a median reduction of fever episodes per year of 72%. Nine patients (16.7%) were considered resistant to colchicine. The presence of generalized lymphadenopathy and, to a lesser extent, exudative tonsillitis was associated with a lack of response to colchicine. ConclusionsWe describe the largest series of patients with syndrome of undifferentiated recurrent fever (SURF) reported in the literature so far. SURF should be considered as a distinct clinical entity in the context of multifactorial autoinflammatory diseases.

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation.Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India.Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed.Results: Data on 107 patients with SAID were collated—of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness.Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

Evaluation of Clinical and Laboratory Characteristics of Patients with PFAPA Syndrome

INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is the most common periodic fever syndrome. The aim of this study was to evaluate the clinical and laboratory findings of patients with PFAPA syndrome at the time of the attack and the response to the given treatments. MATERIALS and METHODS: Sixty-three individuals that applied to the pediatric rheumatology policlinic due to recurrent fever and throat infection and diagnosed with PFAPA syndrome were enrolled in this study. Patients' folders were evaluated retrospectively concerning demographic, clinical and laboratory data. RESULTS: Forty-two (66.7%) of the patients were male, 21 (33.3%) were female. The age of onset of complaints was 2.72±1.59 years. The average delay in diagnosis was 1.71 ± 1.28 years. The remarkable finding which was seen all of our patients was the high fever. Lymphadenitis was detected in 59 (93.7%) of the patients and aphthous stomatitis was found in 56 (88.9%) of the patients. As a laboratory finding, leukocytosis, the increase in C-reactive protein and sedimentation was observed in patients. Fever decreased within a mean of 2.24 ± 1.13 hours after steroid treatment. Another remarkable finding after the first steroid treatment was the resolution of exudative tonsillitis 24 hours after the treatment. CONCLUSIONS: Signs and symptoms of PFAPA syndrome are among the most common signs and symptoms in pediatric outpatient clinics. With increased awareness of PFAPA syndrome in clinicians, patients will be prevented from unnecessary laboratory procedures and medical treatments.

Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study

BackgroundDespite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome.Methods22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5–1 mg on need, based on parents/caregivers’ decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers’ decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment.ResultsPatients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups.ConclusionsWe firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

P61 An innovative multi-speciality clinic for patients with autoinflammatory conditions

Abstract Background Systemic autoinflammatory diseases (SAIDs) are rare, complex, and can often be debilitating. Establishing clinical and genetic diagnoses is equally complex and lengthy, causing significant stress to children and families. Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) recommendations emphasise the importance of access to genetic expertise alongside a tertiary paediatric rheumatology multidisciplinary team. Methods We established a 2-monthly combined clinic for children with diagnosed and suspected autoinflammatory conditions at Birmingham Children’s Hospital (BCH). These are run by a consultant paediatric rheumatologist with special interest in unexplained periodic fever syndromes and autoinflammatory disorders, in collaboration with a consultant clinical geneticist interested in genetic causes for autoinflammation. The BCH paediatric rheumatology department operates a truly multidisciplinary approach with a collocated team. This allows ease of access to clinical nurse specialists, physiotherapy and occupational therapy, as well as effective provision of transitional care, a dedicated research nurse and research coordinator. To avoid multiple appointments and delays in diagnosis, upon receiving referrals for possible SAIDs, a standardised letter along with fever diary, blood forms and instructions for examining clinicians is sent to patients and the referring clinician. In establishing fevers and fever-patterns, possible evidence of inflammation and exclusion of infection prior to initial assessment, the process is streamlined and appointments reduced. A multi-speciality assessment with paediatric rheumatology and genetics is conducted, collaborating with immunology and other appropriate specialists. If SAID is suspected, appropriate panel testing is arranged, followed by whole exome sequencing if results are inconclusive. Patients are also recruited to national and international research studies if relevant, including BCH Rare diseases centre Stars Together Registry &amp; NIHR BioResource rare diseases studies. Results In the past 3 years, the service has seen 96 new patients. Current patients have a variety of diagnoses, including: cryopyrin-associated periodic syndrome (CAPS)(NLRP3 mutations), familial Mediterranean fever (FMF) , TNF receptor-associated periodic syndrome (TRAPS), PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis), ADA2 mutation, NOD-2 mutation, Otulin-related autoinflammatory syndrome (ORAS), Aicardi-Goutieres syndrome (AGS), DNASE1L3 mutation, complement factor I deficiency, C2 deficiency, SLC29A3 mutation, Bechet’s disease and undifferentiated SAIDs. This does not include patients who have primary immunodeficiencies, non-inflammatory vasculopathies or other SAID mimics. Drug therapies include: NSAIDs, short-term corticosteroids, Colchicine, Infliximab, Tocilizumab, Methotrexate, Adalimumab, Mycophenolate mofetil (MMF), Ruxolitinib and Anakinra, all supported by clinical nurse specialists. Conclusion This cohesive service provides single-point access to multidisciplinary paediatric rheumatology and genetics, along with national and international high quality research. A unified approach avoids the need for multiple appointments, allowing prompter diagnosis, initiation of appropriate treatment, and potentially earlier disease control. This aims to prevent disease-related damage, working towards optimal support for families and improving quality of life. A dedicated multi-speciality clinic also provides excellent training opportunities, both between specialities and for junior trainees. Conflicts of Interest The authors declare no conflicts of interest.

PFAPA Syndrome: An atypical Cause of Genital Ulcers in the Adolescent Female

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome affects the pediatric population and presents with recurrent symptoms as described in its name but can also be associated with genital ulceration. Genital ulcers often cause pain and distress. This report will increase provider awareness of genital ulceration with PFAPA, likely increasing accurate diagnoses.

Clinical characteristics of adult patients with autoinflammatory diseases presenting as recurrent fever of unknown origin

Objective To analyze the clinical characteristics of adult patients with autoinflammatory diseases (AUID) presenting as recurrent fever of unknown origin (FUO). Methods The clinical and genetic features of 51 adult patients with recurrent FUO, who were suspected of monogenic AUID admitted in adult AUID center Department of Rheumatology, Peking Union Medical College Hospital from April 2015 to March 2017, were prospectively studied. The clinical phenotypes were compared between patients with pathogenic gene mutations and diagnosed as monogenic AUID (gene-positive group), and those without pathogenic gene mutations (gene-negative group). Results Among 51 patients, there were 26 patients with positive monogenic mutations (51.0%); in addition 6 patients were diagnosed as periodic fever-aphthous stomatitis-pharyngitis-adenitis (PFAPA) syndrome. Finally 32 patients (63.0%) were diagnosed as AUID, including 11 cases of familial Mediterranean fever (34.4%), 5 cases of cryopyrin-associated periodic syndrome (15.6%), 5 cases of NLRP12-autoinflammtory disease (15.6%), 2 cases of Blau syndrome (6.3%), 2 cases of Yao syndrome (6.3%), 1 case of tumor necrosis factor-receptor associated periodic syndrome (3.1%), and 6 cases of PFAPA syndrome (18.8%). Among 25 gene-negative patients except 6 cases of PFAPA syndrome, 9 were diagnosed as other diseases, and the diagnosis of AUID was not confirmed in 10 cases (40.0%). Compared with gene-negative group, gene-positive group had more common childhood-onset (30.8% vs. 8.0%, P=0.041), longer disease duration (11.2±10.1 vs. 6.1±5.9, P=0.031), and more common abdominal pain/diarrhea (42.3% vs.12.0%, P=0.015). There were no significant differences in manifestations such as rash, arthralgia/arthritis, thoracic pain, eye inflammation and oral ulcers between two groups. One patient had family history of AUID, and finally diagnosed as Blau syndrome with NOD2 gene mutation. Conclusion AUID is one of the main causes of adult patients with recurrent FUO. Childhood-onset, long disease duration, abdominal pain/diarrhea, and family history of AUID are more common in patients with AUID pathogenic gene variations. Recognizing these symptom patterns can provide the clues, leading to the initiation of gene testing for patients with recurrent FUO. Adults patients with recurrent FUO suspected of AUID should be referred to specialist physicians in adult AUID center. Key words: Fever of unknown origin; Autoinflammatory diseases; Disease attributers

Marshall Syndrome or PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenopathy) Syndrome

Marshall Syndrome PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) Syndrome is a chronic condition, typically starting 2-5 years old, in which fever occurs periodically (lasts for 3-7 days), accompanied by aphthous-like ulcers, pharyngitis and/or cervical adenitis. The patients have no clinical symptoms between episodes and it is required to exclude all other diseases before confirming the diagnosis. The dramatic response to treatment with steroid helps diagnosing PFAPA. We are presenting the case of an 8 years male patient, with the history of recurrent episodes of fever (onset at the age of two), oral ulcer and difficulty in deglutition who constantly received antibiotic therapy and or antifungal prescribed by different doctors. Clinically the patient was febrile, mildly pale, cervical lymphadenopathy, aphthous ulcers in the tongue with inflamed tonsils, covered with thick exudates and pharyngeal wall was inflamed and folliculated. There was just palpable liver. Laboratory investigations performed but it was without serological confirmation. Throat swab culture was negative. The child received steroid (Prednisolone) with favorable outcome. Subsequently, the patient presented with similar episodes of fever which disappeared within 24 hours of single dose of prednisolone. After Ranitidine (H2 blocker) prophylaxis the patient remains asymptomatic for about one and half years. With our best knowledge this is the first case report of Marshall Syndrome or PFAPA Syndrome in Bangladesh.J Bangladesh Coll Phys Surg 2016; 34(4): 222-224

An Up-to-date Approach to a Patient with a Suspected Autoinflammatory Disease.

Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID.

Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting : Toronto, Canada. 14-17 April 2016.

Author(s): Fotis, Lampros; Shaikh, Nur; Baszis, Kevin; French, Anthony; Tarr, Phillip; Grevich, Sriharsha; Lee, Peggy; Ringold, Sarah; Leroux, Brian; Leahey, Hannah; Yuasa, Megan; Foster, Jessica; Sokolove, Jeremy; Lahey, Lauren; Robinson, William; Newsom, Joshua; Stevens, Anne; Karasawa, Rie; Tamaki, Mayumi; Tanaka, Megumi; Sato, Toshiko; Yudoh, Kazuo; Jarvis, James N; Moncrieffe, Halima; Bennett, Mark F; Tsoras, Monica; Luyrink, Lorie; Xu, Huan; Prahalad, Sampath; Morris, Paula; Dare, Jason; Nigrovic, Peter A; Rosenkranz, Margalit; Becker, Mara; O’Neil, Kathleen M; Griffin, Thomas; Lovell, Daniel J; Grom, Alexei A; Medvedovic, Mario; Thompson, Susan D; Zhu, Lisha; Jiang, Kaiyu; Wong, Laiping; Buck, Michael J; Chen, Yanmin; Moncrieffe, Halima; Brungs, Laura; Liu, Tao; Wang, Ting; Jarvis, James N; Alsaeid, Khaled; Alfailakawi, Jasim; Alenezi, Hamid; Alsaeed, Hazim; Beukelman, Tim; Natter, Marc; Ilowite, Norm; Mieszkalski, Kelly; Burrell, Grendel; Best, Brian; Bristow, Helen; Carr, Shannon; Dennos, Anne; Kaufmann, Rachel; Kimura, Yukiko; Schanberg, Laura; Blier, Peter R; Boneparth, Alexis; Wenderfer, Scott E; Moorthy, L Nandini; Radhakrishna, Suhas M; Sagcal-Gironella, Anna Carmela P; von Scheven, Emily; Gedik, Kader Cetin; Siddique, Salma; Aguiar, Cassyanne L; Erkan, Doruk; Cohen, Ezra; Lee, Yvonne; Dossett, Michelle; Mehta, Darshan; Davis, Roger; Gilbert, Mileka; Goilav, Beatrice; Meidan, Esra

Long-term outcomes of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome

Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis and leukocytosis. Little is known about the true incidence, natural course, pathogenesis, and appropriate therapy in this recently described syndrome. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but long-term clinical follow up is lacking.

The mean platelet volume levels in children with PFAPA syndrome

ObjectivesTo assess whether mean platelet volume (MPV) can be used as a marker in the differential diagnosis of periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. MethodsThe leucocyte counts, thrombocyte counts, and MPV values of 57 children with PFAPA syndrome were recorded during an attack and an attack free period. These values were compared with a healthy control group of 55 individuals. Demographic features of the PFAPA patients group including age, gender and age of first attack, age at diagnosis, frequency of attacks, serum reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also recorded. ResultsThe MPV values of the children with PFAPA both during an attack and attack free period were found significantly lower than the MPV values of healthy control group (p<0.001). Also, the MPV values of the children with PFAPA during an attack were significantly lower than in attack free periods (p<0.001). The MPV values showed no correlation with leucocytes counts, CRP, and ESR during attacks. A 8.30fl [area under the curve (AUC: 0.965)] optimal cutoff value of MPV with a sensitivity of 89.5% and specificity of 92.8% was determined during an attack in children with PFAPA. ConclusionsThe MPV values during an attack and attack free period of patients with PFAPA is lower than in controls. The MPV values may be used as a marker in the differential diagnosis of PFAPA syndrome but more studies are needed and they should be prospective in order to validate this data.

Indications of Pediatric Tonsillectomy

Possible indications for tonsillectomy include sleep apnea and other obstructive sleep-related breathing disorders, recurrent tonsillitis, peritonsillar abscess, periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), and other miscellaneous rare conditions. Over the last century indications have changed, with a decrease in infectious causes and an increase in sleep apnea disorders. Sleep apnea in children is difficult to diagnose short of polysomnography (PSG) which is expensive and disturbing, especially in young children. In sleep apnea confirmed by PSG, tonsillectomy relieves the trouble in close to 80% of patients. What remains unclear is how to diagnose sleep-related breathing disorders without PSG and the efficacy of tonsillectomy in this population. Recurrent tonsillitis is generally poorly documented and randomized studies assessing the efficacy of tonsillectomy are sparse. When frequent infections are present for several years (>7 episodes/1 year, >5/2, >3/3) some benefit from tonsillectomy could be found. If fewer infectious episodes are present, the benefit of tonsillectomy is low. Peritonsillar abscess tends to be treated with quinsy tonsillectomy. Some PFAPA and psoriasis children might benefit from tonsillectomy. Tonsillectomy for other conditions is not warranted.

MEFV Variants in Patients with PFAPA Syndrome in Japan

Background: The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA.Patients and Methods: All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62).Results: In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants.Conclusion: Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.

Auto‐inflammatory syndromes and oral health

Auto-inflammatory diseases (periodic syndromes) are rare childhood-onset disorders which are characterized by fluctuating or recurrent episodes of fever and inflammation affecting serosal surfaces, joints, eyes and/or skin without significant autoantibody production or an identifiable underlying infection. They are disorders of innate immunity and the underlying genetic defect has been identified in most of the syndromes. Diagnosis relies on clinical symptoms and evidence of an elevated acute phase response during attacks, supported by finding mutations in the relevant genes. Several syndromes can lead to systemic AA amyloidosis. Aphthous-like oral ulceration has been reported as one manifestation in several of the syndromes, including periodic fever, aphthous-stomatitis, pharyngitis, adenitis (PFAPA) familial Mediterranean fever (FMF), hyperimmunoglobulinaemia D and periodic fever syndrome, tumour necrosis factor receptor associated periodic syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA). Chronic jaw recurrent osteomyelitis has been recorded in chronic recurrent multifocal osteomyelitis. Advances in the molecular pathogenesis of these syndromes and the regulation of innate immunity have enhanced diagnosis, and rationalized therapies. This article reviews the periodic fever syndromes relevant to oral health and the suggested association of FMF with Behçet's disease.