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Patel JM. Pediatric Systemic Autoinflammatory Disorders: An Overview. Curr Allergy Asthma Rep 2025; 25:23. [PMID: 40299118 DOI: 10.1007/s11882-025-01203-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/30/2025]
Abstract
PURPOSE OF REVIEW Systemic autoinflammatory disorders (SAIDs) are a group of diseases that are characterized by recurrent or persistent unprovoked attacks of inflammation resulting from innate immunity dysregulation and leading to significant sequelae in many cases. The concept of autoinflammatory disorders has been widely studied in the last 28 years since the genetic mutation responsible for familial Mediterranean fever (FMF) was discovered. These disorders are mainly hereditary autoinflammatory diseases with key immunological pathways affected and particularly involving inflammasomes, nuclear factor-κB dysregulation and interferon upregulation. This article serves as an overview of pediatric systemic autoinflammatory disorders, their presentation, workup, complications, and therapeutic management. RECENT FINDINGS Advances in genetic analysis have allowed for the rapid identification of mutations responsible for many autoinflammatory disorders. Advances in biomolecular techniques, which have allowed for identifying key players such as inflammasomes, have led to treatment options that have significantly improved morbidity and mortality in affected patients. This review provides an overview of the proposed pathogenesis, presenting features, potential complications and suggested therapies of systemic autoinflammatory disorders. Providers should have a high clinical suspicion for autoinflammatory disorders in children who present with fever, a heightened inflammatory response and negative evaluation for an infectious, malignant, and autoimmune etiology. Understanding and identifying these disorders in a timely manner and implementing prompt treatment allow for the best possible outcome for these patients.
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Affiliation(s)
- Julisa M Patel
- Allergy-Immunology and Pediatric Rheumatology Division, Department of Pediatrics, Children's Hospital of Georgia, Augusta University Medical Center, 1120 15th Street, BG 102, Augusta, GA, 30912, USA.
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Manthiram K, Ortega-Villa AM, Lapidus S, Bowes M, Romeo T, Garguilo K, Failla L, Srinivasalu H, Mudd P, Ombrello A, Barron K, Kastner DL, Edwards KM. Features Associated with Response to Tonsillectomy in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome in Children. J Pediatr 2025; 282:114559. [PMID: 40122279 DOI: 10.1016/j.jpeds.2025.114559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 03/09/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
OBJECTIVE To identify clinical features associated with response to tonsillectomy among children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and to determine optimal management of children with continued episodes after tonsillectomy. STUDY DESIGN Patients with PFAPA seen at Vanderbilt University Children's Hospital and the National Institutes of Health (NIH) who underwent tonsillectomy were enrolled and queried regarding symptoms before and after surgery. RESULTS Ninety-seven subjects with PFAPA (43 Vanderbilt, 54 NIH) were followed for a median of 49 months following tonsillectomy. Nearly half of participants reported complete resolution of PFAPA episodes (65% at Vanderbilt and 35% at NIH), while 25% had less severe or frequent episodes, 23% had a period of remission with recurrence, and 4% had no change in episodes. By logistic regression, factors associated with a full response to tonsillectomy were episode resolution with glucocorticoid treatment, presence of exudative pharyngitis, absence of rash, and absence of arthralgia/myalgia during pre-tonsillectomy PFAPA flares. Among those requiring treatment for persistent flares post-tonsillectomy, 15/19 (79%) reported improvement with cimetidine or famotidine prophylaxis. CONCLUSION Tonsillectomy remains effective in improving PFAPA flares in most patients. However, unique episode features prior to tonsillectomy appear to be clinical predictors of response to tonsillectomy. Histamine receptor 2 antagonists like cimetidine were effective prophylactic agents for refractory cases post-tonsillectomy. Patients with incomplete response to tonsillectomy may represent a subset of PFAPA with unique factors affecting their pathogenesis.
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Affiliation(s)
- Kalpana Manthiram
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD.
| | - Ana M Ortega-Villa
- Biostatistics Research Branch, Division of Clinical Research, NIAID, NIH, Bethesda, MD
| | - Sivia Lapidus
- Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ
| | - Mary Bowes
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD
| | - Tina Romeo
- National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD
| | - Kathryn Garguilo
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN
| | - Laura Failla
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD
| | - Hemalatha Srinivasalu
- Division of Rheumatology, Department of Pediatrics, George Washington University School of Medicine, Children's National Hospital, Washington, DC
| | - Pamela Mudd
- Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC; Division of Otolaryngology, Department of Surgery, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Amanda Ombrello
- National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD
| | - Karyl Barron
- NIAID, National Institutes of Health, Bethesda, MD
| | - Daniel L Kastner
- National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD
| | - Kathryn M Edwards
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN
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An J, Marwaha A, Laxer RM. Autoinflammatory Diseases: A Review. J Rheumatol 2024; 51:848-861. [PMID: 38879186 DOI: 10.3899/jrheum.2023-1209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/17/2024]
Abstract
Autoinflammatory disease (AID) is a vast spectrum of disorders characterized by recurrent attacks of sterile inflammation. Since the first cloning of the familial Mediterranean fever gene in 1997, there has been a rapid rate of discovery of new AIDs. As of 2022, there have been 485 inborn errors of immunity documented by the International Union of Immunological Societies, for which many display aspects of autoinflammation. The pathophysiology of AIDs is complex. Although many are caused by rare mutations in genes that govern innate immunity, others are polygenic, where disease expression is thought to be triggered by environmental factors in genetically predisposed hosts. AIDs range in prevalence from common entities like gout to ultrarare monogenic diseases. Whereas AIDs were initially studied in pediatric populations, it is now apparent that they can present in adulthood and even in the elderly. AIDs can be clinically challenging given their rarity, as well as the heterogeneity in presentation and underlying etiology. Although the care of AIDs can span medical disciplines, the rheumatologist often plays a central role given the inflammatory nature of these illnesses. In this review, we explore the current understanding of the pathophysiology of these complex conditions and propose a classification system for AIDs. We place an emphasis on AIDs that present to the adult rheumatologist and discuss important AIDs that can mimic more classic rheumatic diseases such as systemic lupus erythematosus and inflammatory arthritis. Finally, we offer an approach to the clinical assessment, diagnosis, and management of AIDs.
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Affiliation(s)
- Jason An
- J. An, MD, MSc, Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, Ontario;
| | - Ashish Marwaha
- A. Marwaha, MD, PhD, Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta
| | - Ronald M Laxer
- R.M. Laxer, MDCM, Division of Rheumatology, Hospital for Sick Children, University of Toronto, and Division of Rheumatology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
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Kozu KT, Nascimento RRNRD, Aires PP, Cordeiro RA, Moura TCLD, Sztajnbok FR, Pereira IA, Almeida de Jesus A, Perazzio SF. Inflammatory turmoil within: an exploration of autoinflammatory disease genetic underpinnings, clinical presentations, and therapeutic approaches. Adv Rheumatol 2024; 64:62. [PMID: 39175060 DOI: 10.1186/s42358-024-00404-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 08/11/2024] [Indexed: 08/24/2024] Open
Abstract
Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still's disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.
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Affiliation(s)
- Kátia Tomie Kozu
- Universidade de Sao Paulo, Faculdade de Medicina (USP FM), Sao Paulo, Brazil
| | | | - Patrícia Pontes Aires
- Universidade Federal de Sao Paulo, Escola Paulista de Medicina (Unifesp EPM), Rua Otonis, 863, Vila Clementino, São Paulo, SP, 04025-002, Brazil
| | | | | | - Flavio Roberto Sztajnbok
- Federal University of Rio de Janeiro: Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Sandro Félix Perazzio
- Universidade de Sao Paulo, Faculdade de Medicina (USP FM), Sao Paulo, Brazil.
- Universidade Federal de Sao Paulo, Escola Paulista de Medicina (Unifesp EPM), Rua Otonis, 863, Vila Clementino, São Paulo, SP, 04025-002, Brazil.
- Division of Immunology and Rheumatology, Fleury Laboratories, Sao Paulo, SP, Brazil.
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Kapustova L, Banovcin P, Bobcakova A, Jurkova Malicherova E, Kapustova D, Petrovicova O, Slenker B, Markocsy A, Oleksak F, Vorcakova K, Jesenak M. The use of ketotifen as long-term anti-inflammatory prophylaxis in children with PFAPA syndrome. Front Immunol 2023; 14:1302875. [PMID: 38143757 PMCID: PMC10748580 DOI: 10.3389/fimmu.2023.1302875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/20/2023] [Indexed: 12/26/2023] Open
Abstract
Introduction Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used. Methods This prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. Results The mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p<0.001). The used dose of ketotifen was 0.08 ± 0.01 mg/kg/day. Mild side effects were observed in four patients (restlessness, irritability, agitation and constipation). Discussion Our data supports the use of ketotifen for long-term prophylaxis in children with PFAPA syndrome with positive effects on the attenuation of disease activity and the prolongation of attack-free periods. Further well-designed studies should confirm the preliminary data.
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Affiliation(s)
- Lenka Kapustova
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Peter Banovcin
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Anna Bobcakova
- Department of Pneumology and Phthisiology, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Eva Jurkova Malicherova
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Daniela Kapustova
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Otilia Petrovicova
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Branislav Slenker
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Adam Markocsy
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Filip Oleksak
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Karolina Vorcakova
- Clinic of Dermatovenerology, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
| | - Milos Jesenak
- Centre for Periodic Fever Syndromes, Department of Paediatrics, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
- Department of Pneumology and Phthisiology, University Hospital in Martin, Jessenius Faculty of Medicine of Comenius University in Bratislava, Martin, Slovakia
- Department of Clinical Immunology and Allergology, University Hospital in Martin, Martin, Slovakia
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Abstract
PURPOSE OF REVIEW Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in childhood. Recent studies report genetic susceptibility variants for PFAPA syndrome and the efficacy of tonsillectomy in a broader cohort of patients with recurrent stereotypical fever. In this review, we highlight the findings of these studies and what they may reveal about the pathogenesis of PFAPA. RECENT FINDINGS Newly identified genetic susceptibility loci for PFAPA suggest that it is a complex genetic disorder linked to Behçet's disease and recurrent aphthous ulcers. Patients who have PFAPA with some features of Behçet's disease have been reported. Moreover, the efficacy of tonsillectomy has now been described in patients who do not meet the full diagnostic criteria for PFAPA, although the immunologic profile in the tonsils is different from those with PFAPA. Factors that predict response to tonsillectomy are also reported. SUMMARY These findings highlight the heterogeneous phenotypes that may be related to PFAPA due to common genetic susceptibility or response to therapy. These relationships raise questions about how to define PFAPA and highlight the importance of understanding of the genetic architecture of PFAPA and related diseases.
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Affiliation(s)
- Kalpana Manthiram
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Onur H, Onur AR. Diagnostic performance of routine blood parameters in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J Clin Lab Anal 2023; 37:e24934. [PMID: 37428978 PMCID: PMC10431407 DOI: 10.1002/jcla.24934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 05/31/2023] [Accepted: 06/06/2023] [Indexed: 07/12/2023] Open
Abstract
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.
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Affiliation(s)
- Hakan Onur
- Department of PediatricsMemorial Private Diyarbakir HospitalDiyarbakirTurkey
| | - Arzu Rahmanali Onur
- Department of Medical MicrobiologyGazi Yasargil Education and Research HospitalDiyarbakirTurkey
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Türkuçar S, Bülbül G, Ünsal E, Özer E, Erdağ TK, Erkoç E, Makay B. Exploring the immunological basis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: immunohistochemical staining features of palatine tonsils. Clin Rheumatol 2023:10.1007/s10067-023-06563-2. [PMID: 36892710 DOI: 10.1007/s10067-023-06563-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/09/2023] [Accepted: 02/24/2023] [Indexed: 03/10/2023]
Abstract
OBJECTIVES Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever syndrome during early childhood period with regular febrile attacks of sterile upper airway inflammation. The cessation of attacks following tonsillectomy points to fundamental role of tonsil tissue on etiopathogenesis of disease, which is not clarified satisfactorily. The aim of this study is to explore the immunological basis of PFAPA by evaluating the cellular properties of tonsils, and microbial exposition such as Helicobacter pylori on tonsillectomy materials. METHODS The paraffinized tonsil samples of 26 PFAPA and 29 control patients with obstructive upper airway disorder were compared in terms of immunohistochemical staining features including CD4, CD8, CD123, CD1a, CD20, and H. pylori. RESULTS The median number of CD8+ cells was 1485 (1218-1287) in PFAPA while it was 1003 (852-1261.5) in control group and the difference was statistically significant (p=0.001). Similarly, CD4+ cell counts were statistically higher in PFAPA group than control (833.5 vs 622). The ratio of CD4/CD8 did not differ between two groups; also, there was no statistically difference in terms of the other immunohistochemical staining results, such as CD20, CD1a, CD123 and H. pylori. CONCLUSION This is the largest number of pediatric tonsillar tissue study of PFAPA patients in current literature and we emphasized the triggering effects of CD8+ and CD4+ T-cells on PFAPA tonsils. KEY POINTS • The cessation of attacks following tonsillectomy points to fundamental role of tonsil tissue on etiopathogenesis of disease, which is not clarified satisfactorily. • In current study, 92.3% of our patients did not experience any attacks following operation similarly with literature. • We observed the increased number of CD4+ and CD8+ T cell counts on PFAPA tonsils compared to control group and emphasized the active role of both CD4+ and CD8+ cells localized on PFAPA tonsils in immune dysregulation. • Some other cell types evaluated in this study such as CD19+ (B cells), CD1a (dendritic cells), and CD123 (IL-3 receptors, for pluripotent stem cells) and H. pylori did not differ in PFAPA patients compared to the control group.
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Affiliation(s)
- Serkan Türkuçar
- Department of Pediatric Rheumatology, Dokuz Eylul University, Izmir, Turkey.
- Division of Pediatric Rheumatology, Konya City Hospital, Karatay/Konya, Turkey.
| | - Göksenil Bülbül
- Department of Medical Pathology, Dokuz Eylul University, Izmir, Turkey
| | - Erbil Ünsal
- Department of Pediatric Rheumatology, Dokuz Eylul University, Izmir, Turkey
| | - Erdener Özer
- Department of Medical Pathology, Dokuz Eylul University, Izmir, Turkey
| | - Taner Kemal Erdağ
- Department of Otorhinolaryngology, Dokuz Eylul University, Izmir, Turkey
| | - Erdal Erkoç
- Department of Otorhinolaryngology, Dokuz Eylul University, Izmir, Turkey
| | - Balahan Makay
- Department of Pediatric Rheumatology, Dokuz Eylul University, Izmir, Turkey
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Gozen ED, Yildiz M, Kara S, Tevetoglu F, Haslak F, Adrovic A, Sahin S, Barut K, Ulkersoy İ, Gücüyener N, Gunalp A, Yener HM, Ada M, Kasapcopur O. 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. Rheumatol Int 2023; 43:137-145. [PMID: 36116090 DOI: 10.1007/s00296-022-05210-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 09/09/2022] [Indexed: 02/02/2023]
Abstract
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.
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Affiliation(s)
- E Deniz Gozen
- Cerrahpasa Medical Faculty Otorhinolaryngology Department, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Mehmet Yildiz
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sinem Kara
- Cerrahpasa Medical Faculty Otorhinolaryngology Department, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Firat Tevetoglu
- Cerrahpasa Medical Faculty Otorhinolaryngology Department, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Fatih Haslak
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Amra Adrovic
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sezgin Sahin
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Kenan Barut
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - İpek Ulkersoy
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Neslihan Gücüyener
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Aybuke Gunalp
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - H Murat Yener
- Cerrahpasa Medical Faculty Otorhinolaryngology Department, İstanbul University-Cerrahpasa, Istanbul, Turkey
| | - Mehmet Ada
- Otorhinolaryngology Department, Acıbadem University, Istanbul, Turkey
| | - Ozgur Kasapcopur
- Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, İstanbul University-Cerrahpasa, Istanbul, Turkey.
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Banday AZ, Joshi V, Arora K, Sadanand R, Basu S, Pilania RK, Jindal AK, Vignesh P, Gupta A, Sharma S, Dhaliwal M, Rawat A, Singh S, Suri D. Challenges in the diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in developing countries—A decade of experience from North India. Front Immunol 2022; 13:958473. [PMID: 36203600 PMCID: PMC9530276 DOI: 10.3389/fimmu.2022.958473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/25/2022] [Indexed: 12/04/2022] Open
Abstract
Background Reports of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome from developing countries are sparse. Recognizing PFAPA is often challenging in these regions due to a higher incidence of infectious illnesses and significant resource constraints. Herein, we present our experience from North India regarding the diagnosis and management of PFAPA syndrome. Methods We reviewed cases of non-monogenic periodic fever syndrome diagnosed at our center from January 2011 to December 2021. A total of 17 children who fulfilled the Marshall criteria for PFAPA syndrome were included. Data regarding basic clinical features, treatment/outcome, and performance of the recently proposed Eurofever/PRINTO and Takeuchi criteria were analyzed. Results Besides recurrent fever, the triad of oral aphthae, pharyngitis, and adenitis was noted in only 18% of patients. Episodes of exudative pharyngitis/tonsillitis were documented in 24%. These figures were lower than the values reported from developed countries. The Takeuchi and Eurofever/PRINTO criteria were fulfilled in 76% and 71% cases, respectively. In addition to antipyretics and supportive care, intermittent steroid therapy was the main treatment modality used. Additional treatment with colchicine (n = 3) and thalidomide (n = 1) was used successfully in a few patients. Before the diagnosis of PFAPA, all patients had received multiple courses of antimicrobials (without microbiological confirmation). These included multiple courses of antibacterials for fever, pharyngotonsillitis, and/or cervical adenitis in all patients and antivirals for fever and aphthous stomatitis in a patient. Empiric antitubercular therapy had also been administered in two patients. Conclusions A significant proportion of patients with PFAPA seem to remain undiagnosed in the Indian subcontinent. Increased awareness and improvement in basic healthcare facilities are crucial in enhancing the recognition of PFAPA, which would eliminate the unprecedented scale of undesirable antimicrobial use in such children.
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Rydenman K, Fjeld H, Hätting J, Berg S, Fasth A, Wekell P. Epidemiology and clinical features of PFAPA: a retrospective cohort study of 336 patients in western Sweden. Pediatr Rheumatol Online J 2022; 20:82. [PMID: 36109811 PMCID: PMC9479440 DOI: 10.1186/s12969-022-00737-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Periodic 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. METHODS The 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. RESULTS In 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. CONCLUSIONS This 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.
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Affiliation(s)
- Karin Rydenman
- Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden. .,Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
| | - Hanna Fjeld
- grid.459843.70000 0004 0624 0259Department of Medical Internship, NU Hospital Group, Trollhättan, Sweden
| | - Josefine Hätting
- grid.416029.80000 0004 0624 0275Department of Pediatrics, Skaraborg Hospital, Lidköping, Sweden
| | - Stefan Berg
- grid.8761.80000 0000 9919 9582Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden ,grid.415579.b0000 0004 0622 1824Department of Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden
| | - Anders Fasth
- grid.8761.80000 0000 9919 9582Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden ,grid.415579.b0000 0004 0622 1824Department of Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden
| | - Per Wekell
- grid.459843.70000 0004 0624 0259Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden ,grid.8761.80000 0000 9919 9582Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
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Kuzu S, Günebakan Ç, Yıldız E, Kahveci OK, Bucak A. Vestibular involvement of PFAPA syndrome. Am J Otolaryngol 2021; 42:102903. [PMID: 33485050 DOI: 10.1016/j.amjoto.2021.102903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/23/2020] [Accepted: 12/29/2020] [Indexed: 11/29/2022]
Abstract
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.
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Affiliation(s)
- Selçuk Kuzu
- Otorhinolaryngology Department, Afyonkarahisar Health Sciences University Medical Faculty, İzmirYolu 8.km, 03300 Afyonkarahisar, Turkey.
| | - Çağlar Günebakan
- Otorhinolaryngology Department, Afyonkarahisar Health Sciences University Medical Faculty, İzmirYolu 8.km, 03300 Afyonkarahisar, Turkey
| | - Erkan Yıldız
- Otorhinolaryngology Department, Şuhut State Hospital, 03200 Şuhut, Afyonkarahisar, Turkey
| | - Orhan Kemal Kahveci
- Otorhinolaryngology Department, Afyonkarahisar Health Sciences University Medical Faculty, İzmirYolu 8.km, 03300 Afyonkarahisar, Turkey
| | - Abdulkadir Bucak
- Otorhinolaryngology Department, Afyonkarahisar Health Sciences University Medical Faculty, İzmirYolu 8.km, 03300 Afyonkarahisar, Turkey
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Kanik A, Eliacik K, Kanik ET, Tekindal MA. Clinical Usefulness of Acute-Phase Markers in Distinguishing between PFAPA and Other Exudative Tonsillitis Causes: A Methodological Study. J Trop Pediatr 2021; 67:6067639. [PMID: 33411886 DOI: 10.1093/tropej/fmaa124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Ali Kanik
- Department of Pediatrics, İzmir Katip Çelebi University, Faculty of Medicine, İzmir, Turkey
| | - Kayı Eliacik
- Department of Pediatrics, Tepecik Teaching and Research Hospital, İzmir, Turkey
| | - Esra Toprak Kanik
- Department of Pediatric Allergy and Immunology, Dr. Behcet Uz Childrens Hospital, İzmir, Turkey
| | - Mustafa Agah Tekindal
- Faculty of Veterinary Medicine, Department of Biostatistics, Selcuk University, Konya, Turkey
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Tejesvi MV, Tapiainen T, Vänni P, Uhari M, Suokas M, Lantto U, Koivunen P, Renko M. Tonsil Mycobiome in PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) Syndrome: A Case-Control Study. Front Cell Infect Microbiol 2021; 10:616814. [PMID: 33585283 PMCID: PMC7873641 DOI: 10.3389/fcimb.2020.616814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/08/2020] [Indexed: 11/27/2022] Open
Abstract
Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in children with unknown etiology, effectively treated with tonsillectomy. Earlier we have shown that tonsil microbiome is different in patients with PFAPA as compared to that in controls. Recently, fungal microbiome, mycobiome, has been linked to the pathogenesis of inflammatory diseases. We now investigated the role of mycobiome of tonsils in PFAPA. Random forest classification, a machine learning approach, was used for the analysis of mycobiome data. We examined tonsils from 30 children with PFAPA and 22 control children undergoing tonsillectomy for non-infectious reasons. We identified 103 amplicon sequence variants, mainly from two fungal phyla, Ascomycota and Basidiomycota. The mean relative abundance of Candida albicans in the tonsil mycobiome was 11% (95% CI: 19 to 27%) in cases and 3.4 % (95% CI: -0.8% to 8%) in controls, p =0.104. Mycobiome data showed no statistical difference in differentiating between PFAPA cases and controls compared to a random chance classifier (area under the curve (AUC) = 0.47, SD = 0.05, p = 0.809). In conclusion, in this controlled study, tonsillar mycobiome in children with PFAPA syndrome did not differ from that of the controls.
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Affiliation(s)
- Mysore V Tejesvi
- Ecology and Genetics, Faculty of Science, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Genobiomics LLC, Oulu, Finland
| | - Terhi Tapiainen
- Biocenter Oulu, University of Oulu, Oulu, Finland.,PEDEGO Research Unit, University of Oulu, Oulu, Finland.,Department of Paediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland
| | - Petri Vänni
- Genobiomics LLC, Oulu, Finland.,PEDEGO Research Unit, University of Oulu, Oulu, Finland
| | - Matti Uhari
- Biocenter Oulu, University of Oulu, Oulu, Finland.,PEDEGO Research Unit, University of Oulu, Oulu, Finland
| | - Marko Suokas
- Ecology and Genetics, Faculty of Science, University of Oulu, Oulu, Finland
| | - Ulla Lantto
- PEDEGO Research Unit, University of Oulu, Oulu, Finland.,Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland
| | - Petri Koivunen
- PEDEGO Research Unit, University of Oulu, Oulu, Finland.,Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland
| | - Marjo Renko
- PEDEGO Research Unit, University of Oulu, Oulu, Finland.,Department of Paediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
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Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome in Children: Retrospective Evaluation of 82 Cases. ANADOLU KLINIĞI TIP BILIMLERI DERGISI 2020. [DOI: 10.21673/anadoluklin.698210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Long-term management of patients with PFAPA syndrome. Eur Arch Otorhinolaryngol 2020; 277:2335-2339. [PMID: 32239314 DOI: 10.1007/s00405-020-05943-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/23/2020] [Indexed: 10/24/2022]
Abstract
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.
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Yildiz M, Adrovic A, Tasdemir E, Baba-Zada K, Aydin M, Koker O, Sahin S, Barut K, Kasapcopur O. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int 2020; 40:57-64. [PMID: 31352561 DOI: 10.1007/s00296-019-04391-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/21/2019] [Indexed: 01/03/2023]
Abstract
Familial Mediterranean fever (FMF) is A common periodic fever syndrome. The causative gene of the FMF is named Mediterranean Fever gene (MEFV). Increased inflammation in FMF may play a role as a trigger for the development of some diseases. The objective of the study is to evaluate the frequency of comorbid disorders in children followed up with diagnosis of FMF. Additionally, we aimed to assess the association between FMF and other inflammatory conditions in a large pediatric FMF cohort. A total of 686 FMF patients were included in the cross-sectional study. A questionnaire including questions about characteristics of fever episodes, presence of arthralgia, arthritis, abdominal pain, chest pain during and co-existence of any other disease diagnosed by a physician was filled out by face-to-face interviews with patients or their parents. Female-male ratio was 0.85. Median age at the time of study, age at disease onset and at the time of diagnosis were 12.9 (1.7-22.3), 3 (0.08-17), and 6 (0.75-17) years, respectively. In 130 (18.9%) FMF patients we detected co-existing inflammatory condition. The most common co-existing diseases were: juvenile idiopathic arthritis 42 (6.1%), asthma/reactive airway disease 29 (4.2%), Henoch-Schönlein purpura 20 (2.9%), uveitis 12 (1.7%) and inflammatory bowel disease 10 (1.4%). Except for asthma/reactive airway disease and inflammatory bowel disease, there was no significant difference regarding the type of MEFV gene mutation. We have reported increased frequencies of various inflammatory conditions and decreased frequency of asthma in patients with FMF.
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Affiliation(s)
- Mehmet Yildiz
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Amra Adrovic
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Emre Tasdemir
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Khanim Baba-Zada
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Muhammed Aydin
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Oya Koker
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Sezgin Sahin
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Kenan Barut
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey
| | - Ozgur Kasapcopur
- Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey.
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Burton MJ, Pollard AJ, Ramsden JD, Chong L, Venekamp RP, Cochrane ENT Group. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev 2019; 12:CD008669. [PMID: 31886897 PMCID: PMC6953364 DOI: 10.1002/14651858.cd008669.pub3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane Review first published in 2010 and previously updated in 2014. OBJECTIVES To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) compared with non-surgical treatment in the management of children with PFAPA. SEARCH METHODS The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2019, Issue 4); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 15 October 2019. SELECTION CRITERIA Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures expected by Cochrane. The primary outcomes were the proportion of children whose symptoms have completely resolved and complications of surgery (haemorrhage and number of days of postoperative pain). Secondary outcomes were: number of episodes of fever and the associated symptoms; severity of episodes; use of corticosteroids; absence or time off school; quality of life. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported. AUTHORS' CONCLUSIONS The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.
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Affiliation(s)
- Martin J Burton
- Cochrane UKSummertown Pavilion18 ‐ 24 Middle WayOxfordUKOX2 7LG
| | - Andrew J Pollard
- Children's HospitalDepartment of Paediatrics, University of OxfordOxfordUKOX3 9DU
| | - James D Ramsden
- Oxford Radcliffe Hospitals NHS TrustDepartment of Otolaryngology ‐ Head and Neck SurgeryLevel LG1, West WingJohn Radcliffe HospitalOxfordUKOX3 9DU
| | | | - Roderick P Venekamp
- University Medical Center Utrecht, Utrecht UniversityJulius Center for Health Sciences and Primary Care & Department of OtorhinolaryngologyHeidelberglaan 100UtrechtNetherlands3508 GA
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Características y evolución de una cohorte de niños con síndrome PFAPA en la Comunidad de Madrid. ACTA ACUST UNITED AC 2019; 15:355-359. [DOI: 10.1016/j.reuma.2017.10.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 10/21/2017] [Accepted: 10/28/2017] [Indexed: 12/12/2022]
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Renko M, Lantto U, Tapiainen T. Towards better diagnostic criteria for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Acta Paediatr 2019; 108:1385-1392. [PMID: 30901126 DOI: 10.1111/apa.14792] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/04/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022]
Abstract
AIM Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most common cause of a periodic fever in childhood. The exact pathogenesis and the aetiology of PFAPA are still unknown. METHODS We conducted a non-systematic review of published articles about PFAPA syndrome and summarised the evidence for diagnostic criteria and treatment options for PFAPA. RESULTS The first proposed diagnostic criteria for PFAPA, in addition to periodic fever, included aphthous stomatitis, pharyngitis or cervical lymphadenitis in children younger than five years at the beginning of the symptoms. C-reactive protein (CRP) levels and leucocyte counts increase in most patients during episodes. Recent research reveals that tonsillectomy provides an immediate and long-lasting cure for PFAPA, even in the absence of classic criteria of aphthous stomatitis, pharyngitis or cervical adenitis and in children older than five years. CONCLUSION We suggest that PFAPA can be diagnosed in children with at least five regularly occurring fever episodes without any other explanation, even in the absence of aphthous stomatitis, pharyngitis or cervical lymphadenitis and also in children older than five years.
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Affiliation(s)
- Marjo Renko
- Department of Paediatrics University of Eastern Finland and Kuopio University Hospital Kuopio Finland
- PEDEGO Research Unit University of Oulu Oulu Finland
| | - Ulla Lantto
- PEDEGO Research Unit University of Oulu Oulu Finland
- Department of Otorhinolaryngology Oulu University Hospital Oulu Finland
| | - Terhi Tapiainen
- PEDEGO Research Unit University of Oulu Oulu Finland
- Department of Children and Adolescents Oulu University Hospital Oulu Finland
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Takeuchi Y, Shigemura T, Kobayashi N, Nagumo H, Furumoto M, Ogasawara K, Fujii H, Takizawa M, Soga T, Matoba H, Masumoto J, Fukushima K, Migita K, Ojima T, Umeda Y, Agematsu K. Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Int J Rheum Dis 2019; 22:1489-1497. [PMID: 31131563 DOI: 10.1111/1756-185x.13610] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 05/03/2019] [Accepted: 05/05/2019] [Indexed: 11/29/2022]
Abstract
AIM The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. METHOD The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. RESULTS Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. CONCLUSION Our new criteria are useful for diagnosing PFAPA.
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Affiliation(s)
- Yusuke Takeuchi
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonari Shigemura
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Norimoto Kobayashi
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Haruo Nagumo
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Kyo Ogasawara
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hitomi Fujii
- Department of Pediatrics, Azumino Red Cross Hospital, Azumino, Japan
| | - Masahiro Takizawa
- Department of Pediatrics, Azumino Red Cross Hospital, Azumino, Japan
| | - Takashi Soga
- Children's Medical Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan
| | - Hisanori Matoba
- Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan
| | - Junya Masumoto
- Department of Pathology, Proteo-Science Center and Graduate School of Medicine, Ehime University, Toon, Japan
| | - Keitaro Fukushima
- Department of Pediatrics, Dokkyo Medical University, Shimotsuga, Japan
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Toshiyuki Ojima
- Department of Community Health and Preventive Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoh Umeda
- Children's Medical Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan
| | - Kazunaga Agematsu
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.,Children's Medical Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan.,Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan
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22
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Sparud-Lundin C, Berg S, Fasth A, Karlsson A, Wekell P. From uncertainty to gradually managing and awaiting recovery of a periodic condition- a qualitative study of parents´ experiences of PFAPA syndrome. BMC Pediatr 2019; 19:99. [PMID: 30961562 PMCID: PMC6454720 DOI: 10.1186/s12887-019-1458-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 03/13/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The prevalence of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is unknown. Although an uncommon condition, it is considered to be the most common autoinflammatory disease among children in many parts of the world. The knowledge of the consequences of the recurrent fever episodes for the child and its family are limited. This study explores the experiences of parents regarding the impact of the disease on the child's general well-being, the family's situation and how the family handles the associated challenges. METHODS A qualitative approach was used, applying a modified version of Grounded theory for design, data collection and analysis. Data was collected from two different sources: communication between parents of children with PFAPA in a closed Facebook group and face-to face interviews with one of the parents of children diagnosed with PFAPA (6 mothers and 2 fathers). RESULTS Parents described a lengthy process of how everyday life becomes affected by their child's recurrent fever episodes. This process is depicted in the following Grounded Theory core category: From uncertainty to gradually managing and awaiting recovery. The categories Uncertainty, Assurance, Gradually managing and Recovery describe the experienced illness trajectory. The illness representation illustrates the experiences/impacts of the periodic condition in the subcategories: Harmlessness-Severity, Disclosure of diagnosis, Impact on daily life and Regularity-Unpredictability. The children's well-being was highly affected by the symptoms during episodes. Parents experienced increased stress with constant fatigue, social constraints of family life and restricted career opportunities. Nevertheless, hope of recovery was constantly present. CONCLUSIONS PFAPA is associated with a considerable burden on the child and the parents in daily life. Obtaining a diagnosis enables parents to move from a state of uncertainty towards a sense of coherence while awaiting recovery. Because of limited general knowledge of the condition and its impact on daily life, health care professionals need to become aware of the parents' efforts to mitigate the consequences of the recurrent episodes for the child and for the family as a whole.
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Affiliation(s)
- C Sparud-Lundin
- Institute of Health and Care Sciences, Sahlgrenska Academy, University of Gothenburg, Box 457, SE-, 405 30, Gothenburg, Sweden.
| | - S Berg
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - A Fasth
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - A Karlsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - P Wekell
- Department of Pediatrics, NU-Hospital Group, Uddevalla, Sweden.,Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
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23
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Bueno LA, Paiva DM, Carvalho PHPD. Síndrome PFAPA: Diagnóstico e Tratamento na Atenção Primária à Saúde. REVISTA BRASILEIRA DE MEDICINA DE FAMÍLIA E COMUNIDADE 2019. [DOI: 10.5712/rbmfc14(41)1815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Objetivo: Apresentar informações sobre o diagnóstico e tratamento da síndrome PFAPA na Atenção Primária à Saúde. Métodos: Revisão sistemática de literatura baseada na recomendação PRISMA e realizada nas bases de dados Scielo, Lilacs, Medline, IBECS e PubMed, incluindo estudos publicados no período de 2004 a 2018, além da consulta a outros documentos específicos da síndrome PFAPA. Resultados: Após busca e seleção, foram incluídos 31 artigos. Avaliação e Diagnóstico: A síndrome PFAPA acomete principalmente crianças, sendo caracterizada por febre periódica acompanhada por faringite, estomatite aftosa e/ou adenite cervical. Seu diagnóstico é clínico e por exclusão, baseado em critérios estabelecidos. Recomendações: Os episódios costumam responder a prednisona e, em graus variáveis, a cimetidina e colchicina. Casos refratários e acompanhados de hipertrofia tonsilar são candidatos a tonsilectomia, devendo ser encaminhados à avaliação otorrinolaringológica.
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24
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Batu ED. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int 2019; 39:957-970. [PMID: 30798384 DOI: 10.1007/s00296-019-04257-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 02/14/2019] [Indexed: 01/20/2023]
Abstract
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome of early childhood with increasing number of adult-onset cases. Although it is a self-limited disease, it may negatively affect the quality of life. The aim of this review is to present a detailed analysis of PFAPA syndrome and an algorithm for diagnosis, therapeutic options, and evaluation of outcome. A comprehensive literature search was conducted through the Cochrane Library, Scopus, and MEDLINE/PubMed databases. The main topics covered are the epidemiology, clinical manifestations, diagnosis, differential diagnosis, etiopathogenesis, genetics, management, disease course and prognosis, disease in adults, unsolved issues, and unmet needs in PFAPA. The diagnosis of PFAPA is mainly based on clinical classification criteria. The most relevant hypothesis for pathogenesis is that dysregulated immune system in a genetically predisposed individual responds to a yet unidentified trigger in an exaggerated way. The pedigree analyses suggest a genetic background for the disease with an autosomal dominant pattern of inheritance. For management, single-dose corticosteroids during attacks and tonsillectomy remain the most effective therapies, while colchicine is a promising option to decrease attack frequency. There remain unsolved issues in PFAPA such as the exact etiopathogenesis and genetic background, the reason why the inflammation is restricted to the oropharyngeal lymphoid tissue, reasons for clock-work regularity of attacks, and self-limited disease course. There is need for a valid diagnostic criteria set with a high performance for both children and adults and consensus on management of PFAPA.
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Affiliation(s)
- Ezgi Deniz Batu
- Division of Rheumatology, Department of Pediatrics, Ankara Training and Research Hospital, University of Health Sciences, 06100, Ankara, Turkey.
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25
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Wekell P. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome - PFAPA syndrome. Presse Med 2019; 48:e77-e87. [PMID: 30683466 DOI: 10.1016/j.lpm.2018.08.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/07/2018] [Indexed: 01/04/2023] Open
Abstract
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a complex autoinflammatory disease with a clinical phenotype characterised by recurrent episodes of fever, systemic inflammation and symptoms and signs depicted in disease acronym. Although PFAPA is the most common autoinflammatory disease among children in many parts of the world, the condition is still an enigma, which include the regular episodes, the prompt responses to corticosteroids, the genetic bases for the familial clustering and therapeutic effects of tonsillectomy. This review explores PFAPA syndrome with the aim of describing the current clinical and scientific understanding of the condition.
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Affiliation(s)
- Per Wekell
- Department of Pediatrics, NU-Hospital Group, 45180 Uddevalla, Sweden; Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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26
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Adrovic A, Sahin S, Barut K, Kasapcopur O. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 2019; 39:29-36. [PMID: 30019226 DOI: 10.1007/s00296-018-4105-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 07/13/2018] [Indexed: 11/30/2022]
Abstract
Autoinflammatory diseases are characterized by fever attacks of varying durations, associated with variety of symptoms including abdominal pain, lymphadenopathy, polyserositis, arthritis, etc. Despite the diversity of the clinical presentation, there are some common features that make the differential diagnosis of the autoinflammatory diseases challenging. Familial Mediterranean fever (FMF) is the most commonly seen autoinflammatory conditions, followed by syndrome associated with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). In this review, we aim to evaluate disease characteristics that make a diagnosis of FMF and PFAPA challenging, especially in a regions endemic for FMF. The ethnicity of patient, the regularity of the disease attacks, and the involvement of the upper respiratory systems and symphonies could be helpful in differential diagnosis. Current data from the literature suggest the use of biological agents as an alternative for patients with FMF and PFAPA who are non-responder classic treatment options. More controlled studies are needed to evaluate the efficacy and safety of this strategy.
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Affiliation(s)
- Amra Adrovic
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Sezgin Sahin
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Kenan Barut
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Ozgur Kasapcopur
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.
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27
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Grimwood C, Kone-Paut I, Piram M, Rossi-Semerano L, Hentgen V. Health-related quality of life in children with PFAPA syndrome. Orphanet J Rare Dis 2018; 13:132. [PMID: 30092788 PMCID: PMC6085641 DOI: 10.1186/s13023-018-0878-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 07/19/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Conventionally, PFAPA syndrome is considered as a benign disease compared to other recurrent fevers because it completely passes before adulthood. However, in our clinical practice, fever episodes have a huge impact on daily activities. METHODS Observational cohort study using the Pediatric Quality of Life Inventory (PedsQL™ 4.0) Generic Core and Fatigue Scales. PedsQL™ uses a modular approach to measure the HRQOL in children with acute and chronic health conditions. We used pediatric FMF patients as the control group. RESULTS We included 33 children with PFAPA and compared them to 27 FMF patients matched for age: preschool-age children (2 to 7 years) and school-age children and youths (8 to18 years). PedsQL™ self-reported scores of children with PFAPA were systematically lower than those of FMF peers for general quality of life and physical and psychosocial functioning (significant only in the preschool-age group). PedsQL™ self-reported fatigue scores of children with PFAPA were significantly lower than those of FMF peers for both preschoolers and school-age children and youths. Parent proxy-reports were not significantly different, even though scores were systematically lower for the parents of PFAPA children. CONCLUSION Our study demonstrates, for the first time, that the wellbeing of PFAPA children is poor, with a major impact on psychosocial functioning and increased fatigue. The quality of life of PFAPA children appears to be even lower than that of FMF patients, for whom a lower than normal HRQOL has already been demonstrated.
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Affiliation(s)
- Claire Grimwood
- Department of Pediatrics, Ambroise Paré hospital, University of Versailles SQY, 9 avenue Charles de Gaulle, 92100 Boulogne Billancourt, France
| | - Isabelle Kone-Paut
- CEREMAIA, Pediatric rheumatology, Bicêtre hospital, APHP, university of Paris Sud, Le Kremlin Bicêtre, France
| | - Maryam Piram
- CEREMAIA, Pediatric rheumatology, Bicêtre hospital, APHP, university of Paris Sud, Le Kremlin Bicêtre, France
| | - Linda Rossi-Semerano
- CEREMAIA, Pediatric rheumatology, Bicêtre hospital, APHP, university of Paris Sud, Le Kremlin Bicêtre, France
| | - Véronique Hentgen
- CEREMAIA, departement of pediatrics, Versailles hospital, Versailles Le Chenay, France
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28
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An Underlooked Cause of Periodic Fever (PFAPA) in an Adult Patient with No Response to Tonsillectomy. Case Rep Rheumatol 2018; 2018:6580835. [PMID: 29854539 PMCID: PMC5954889 DOI: 10.1155/2018/6580835] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 03/26/2018] [Indexed: 12/05/2022] Open
Abstract
Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is an autoinflammatory disease manifested as recurrent febrile episodes associated with one of the following cardinal features: aphthous ulceration, pharyngitis, and cervical adenitis. It was initially described in children and thought to be a disease of pediatric age group. Few adult cases were also reported in the literature. We describe the case of a 39-year-old female affected by PFAPA who presented with a history of febrile episodes associated with aphthous ulceration, stomatitis, and tonsillitis for 4 years. The febrile episodes occurred at a regular interval of 4 weeks and resolved within 5 days. The patient underwent tonsillectomy without any significant improvement. The patient responded only to a single high dose of steroid during the attack. Although PFAPA was initially thought to be a disease of pediatric age group, it should be considered in patients with recurrent febrile illness in all age groups.
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29
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Førsvoll J, Øymar K. The role of tonsillectomy in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome; a literature review. BMC EAR, NOSE, AND THROAT DISORDERS 2018; 18:3. [PMID: 29483843 PMCID: PMC5824547 DOI: 10.1186/s12901-017-0049-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/20/2017] [Indexed: 11/10/2022]
Abstract
Background Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge of the effect of TE or ATE in the PFAPA syndrome. Methods A search of PubMed, Medline, EMBASE and Cochrane was conducted for papers written in English dated from 1 January 1987 to 31 December 2016. The search included all studies reporting outcomes after TE or ATE from children aged 0 to 18 years with PFAPA. Results Two randomized controlled trials reported significantly faster resolution of febrile episodes after TE or ATE in children with PFAPA compared to controls (non-surgery groups). We identified 28 case series including 555 children with PFAPA. The diagnosis was set prospectively before surgery in 440 children and retrospectively after surgery in 115 of the children. TE or ATE had a curative effect in 509 of the 555 children with PFAPA (92%), but few studies were of high quality. Conclusion TE or ATE may have a curative effect on children with PFAPA, but the evidence is of moderate quality. Further high-quality randomized controlled studies are still needed. Electronic supplementary material The online version of this article (10.1186/s12901-017-0049-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jostein Førsvoll
- 1Department of Paediatrics, Stavanger University Hospital, PO BOX 8100, 4068 Stavanger, Norway.,2Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Knut Øymar
- 1Department of Paediatrics, Stavanger University Hospital, PO BOX 8100, 4068 Stavanger, Norway.,2Department of Clinical Science, University of Bergen, Bergen, Norway
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30
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Harel L, Hashkes PJ, Lapidus S, Edwards KM, Padeh S, Gattorno M, Marshall GS. The First International Conference on Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis Syndrome. J Pediatr 2018; 193:265-274.e3. [PMID: 29246466 DOI: 10.1016/j.jpeds.2017.10.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Liora Harel
- Rheumatology Unit, Schneider Children's Medical Center of Israel, Petach Tiva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Philip J Hashkes
- Pediatric Rheumatology Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel; Hadassah Hebrew University School of Medicine, Jerusalem, Israel
| | - Sivia Lapidus
- Pediatric Rheumatology Division, Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ; Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA
| | - Kathryn M Edwards
- Department of Pediatrics and Vaccine Research Program, Vanderbilt University School of Medicine, Nashville, TN; Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN
| | - Shai Padeh
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Italy
| | - Marco Gattorno
- Rheumatology Unit, Department of Pediatrics G, Gaslini Scientific Institute for Children, Genoa, Italy; University of Genoa, Genoa, Italy
| | - Gary S Marshall
- Divison of Pediatric Infectious Diseases, University of Louisville School of Medicine, Louisville, KY
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31
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Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cınar O, Kasapcopur O. PFAPA Syndrome in a Population with Endemic Familial Mediterranean Fever. J Pediatr 2018; 192:253-255. [PMID: 29031862 DOI: 10.1016/j.jpeds.2017.08.078] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/22/2017] [Accepted: 08/30/2017] [Indexed: 01/14/2023]
Abstract
We reviewed the medical records of patients with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) to investigate the clinical course, treatment response, and association with MEFV gene mutation. Familial Mediterranean fever should be considered in patients with PFAPA who do not respond to adenotonsillectomy.
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Affiliation(s)
- Esra Pehlivan
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Amra Adrovic
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Sezgin Sahin
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Kenan Barut
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Ovgu Kul Cınar
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Ozgur Kasapcopur
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.
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32
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Unique histologic features of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Clin Rheumatol 2017; 37:1309-1317. [PMID: 28748511 DOI: 10.1007/s10067-017-3773-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/23/2017] [Accepted: 07/18/2017] [Indexed: 01/10/2023]
Abstract
The objective of this study is to compare the histology and immune cell composition of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome to those from patients with obstructive sleep apnea (OSA). Patients with PFAPA and age-matched controls with OSA who had undergone tonsillectomy at Vanderbilt Children's Hospital were recruited. After informed consent, archival paraffin-embedded, formalin-fixed tonsil tissues were obtained. Sizes of major histologic regions were measured. Cores of germinal centers, crypts, and squamous epithelium were assembled on a tissue microarray for immunohistochemical staining and digital image analysis. Features of tonsils from PFAPA and OSA patients were compared with Wilcoxon signed-rank test. Samples from 16 cases with PFAPA and 16 controls with OSA were evaluated. Tonsils from PFAPA cases had significantly smaller germinal centers (0.18 vs. 0.47 mm2, p = 0.001) and wider squamous epithelia (176 vs. 138 μm, p = 0.008) than those of OSA patients. The percentages of B and T lymphocytes and myeloid cells were comparable in germinal centers, crypts, and squamous epithelia from PFAPA and OSA patients. Longer time from the last febrile episode in PFAPA cases was associated with larger germinal center area (Spearman's rho = 0.61, p = 0.02). We found differences in the sizes of germinal centers and squamous epithelia in tonsils of patients with PFAPA and OSA, but the cellular compositions within these areas were comparable. Our results suggest that tonsils from patients with PFAPA change histologically over time with enlarging germinal centers following a febrile episode. Additional studies are needed to understand the pathogenesis of PFAPA.
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33
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Yamagami K, Nakamura T, Nakamura R, Hanioka Y, Seki K, Chiba H, Kobayashi K, Agematsu K. Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA. Mod Rheumatol 2017; 27:356-359. [PMID: 28001092 DOI: 10.1080/14397595.2017.1267173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Familial Mediterranean fever (FMF) can be classified into typical and incomplete/atypical types. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome-like symptoms have been found in atypical type carrying P369S-R408Q mutations in the responsible gene MEFV. A 28-year-old female with recurrent fever and her young sisters and mother, all of whom had tonsillectomy for tonsillitis, carried heterozygous alterations involving E148Q/P369S/R408Q. A diagnosis of atypical FMF, MEFV exon3 variants with PFAPA syndrome-like symptoms, was made.
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Affiliation(s)
- Keiko Yamagami
- a Department of Internal Medicine , Osaka City General Hospital , Osaka , Japan
| | - Tomoyuki Nakamura
- a Department of Internal Medicine , Osaka City General Hospital , Osaka , Japan
| | - Ryota Nakamura
- a Department of Internal Medicine , Osaka City General Hospital , Osaka , Japan
| | - Yusuke Hanioka
- a Department of Internal Medicine , Osaka City General Hospital , Osaka , Japan
| | - Kaori Seki
- a Department of Internal Medicine , Osaka City General Hospital , Osaka , Japan
| | - Hiroshi Chiba
- b Department of General Medicine , Hachinohe City Hospital , Hachinohe , Japan , and
| | - Keiko Kobayashi
- c Department of Infection and Host Defense, Graduate School of Medicine , Shinshu University , Matsumoto , Japan
| | - Kazunaga Agematsu
- c Department of Infection and Host Defense, Graduate School of Medicine , Shinshu University , Matsumoto , Japan
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34
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Windfuhr JP. Indications for tonsillectomy stratified by the level of evidence. GMS CURRENT TOPICS IN OTORHINOLARYNGOLOGY, HEAD AND NECK SURGERY 2016; 15:Doc09. [PMID: 28025609 PMCID: PMC5169082 DOI: 10.3205/cto000136] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Background: One of the most significant clinical trials, demonstrating the efficacy of tonsillectomy (TE) for recurrent throat infection in severely affected children, was published in 1984. This systematic review was undertaken to compile various indications for TE as suggested in the literature after 1984 and to stratify the papers according to the current concept of evidence-based medicine. Material and methods: A systematic Medline research was performed using the key word of "tonsillectomy" in combination with different filters such as "systematic reviews", "meta-analysis", "English", "German", and "from 1984/01/01 to 2015/05/31". Further research was performed in the Cochrane Database of Systematic Reviews, National Guideline Clearinghouse, Guidelines International Network and BMJ Clinical Evidence using the same key word. Finally, data from the "Trip Database" were researched for "tonsillectomy" and "indication" and "from: 1984 to: 2015" in combination with either "systematic review" or "meta-analysis" or "metaanalysis". Results: A total of 237 papers were retrieved but only 57 matched our inclusion criteria covering the following topics: peritonsillar abscess (3), guidelines (5), otitis media with effusion (5), psoriasis (3), PFAPA syndrome (6), evidence-based indications (5), renal diseases (7), sleep-related breathing disorders (11), and tonsillitis/pharyngitis (12), respectively. Conclusions: 1) The literature suggests, that TE is not indicated to treat otitis media with effusion. 2) It has been shown, that the PFAPA syndrome is self-limiting and responds well to steroid administration, at least in a considerable amount of children. The indication for TE therefore appears to be imbalanced but further research is required to clarify the value of surgery. 3) Abscesstonsillectomy as a routine is not justified and indicated only for cases not responding to other measures of treatment, evident complications, or with a significant history of tonsillitis. In particular, interval-tonsillectomy is not justified as a routine. 4) TE, with or without adenoidectomy, is efficacious to resolve sleep-related breathing disorders resulting from (adeno)tonsillar hypertrophy in children. However, the benefit is reduced by co-morbidities, such as obesity, and further research is required to identify prognostic factors for this subgroup of patients. Further research is indicated to clarify selection criteria not only for this subpopulation that may benefit from less invasive procedures such as tonsillotomy in the long-term. 5) Further trials are also indicated to evaluate the efficacy of TE on the clinical course in children with psoriasis guttata as well as on psoriasis vulgaris in adults, not responding to first-line therapy. 6) Conflicting results were reported concerning the role of TE in the concert to treat Ig-A nephropathy, mandating further clinical research. 7) Most importantly, randomized-controlled clinical trials with an adequate long-term follow-up are desirable to clarify the benefit of TE in patients with recurrent episodes of tonsillitis, with or without pharyngitis. Factors like age, spontaneous healing rate and postoperative quality of life have to be included when comparing TE with antibiotic therapy.
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Affiliation(s)
- Jochen P. Windfuhr
- Department of Otolaryngology, Head & Neck Surgery, Allergology, Kliniken Maria Hilf, Mönchengladbach, Germany
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Lantto U, Koivunen P, Tapiainen T, Renko M. Long-Term Outcome of Classic and Incomplete PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) Syndrome after Tonsillectomy. J Pediatr 2016; 179:172-177.e1. [PMID: 27692464 DOI: 10.1016/j.jpeds.2016.08.097] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 08/19/2016] [Accepted: 08/30/2016] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To compare the effectiveness of tonsillectomy and the long-term outcome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome in patients fulfilling the classic diagnostic criteria and in those with regularly recurring fever as the only symptom or with onset of symptoms after age 5 years or both. STUDY DESIGN We reviewed the medical records of 3852 children who underwent tonsillectomy between 1990 and 2007 and identified 108 children who did so because of regularly recurring fevers. The patients were invited to an outpatient visit and were classified into 2 groups: those who met (N = 58) and those who did not meet (N = 50) Thomas diagnostic criteria. We then compared the clinical profile and outcome of PFAPA symptoms after tonsillectomy between the 2 groups. RESULTS In the group that met Thomas criteria, 97% (56/58) had complete resolution of fever episodes after tonsillectomy; in the group that did not meet Thomas criteria (50/50) had complete resolution of fever episodes after tonsillectomy (P = .25). The clinical profile of the periodic fevers and the occurrence of other illnesses during follow-up were similar in both groups. Thomas criteria identified 56 of 106 patients responding to tonsillectomy. CONCLUSIONS Tonsillectomy was an effective treatment for patients with regularly recurring fever episodes who failed to meet the classic Thomas criteria. We suggest that PFAPA syndrome should be suspected and tonsillectomy considered in children with a late onset of symptoms (>5 years of age) or when fever is the only symptom during the episodes.
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Affiliation(s)
- Ulla Lantto
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, University of Oulu, Oulu, Finland; Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland.
| | - Petri Koivunen
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, University of Oulu, Oulu, Finland; Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland
| | - Terhi Tapiainen
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Marjo Renko
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
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Wekell P, Karlsson A, Berg S, Fasth A. Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Acta Paediatr 2016; 105:1140-51. [PMID: 27426283 PMCID: PMC5095866 DOI: 10.1111/apa.13531] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 06/09/2016] [Accepted: 07/14/2016] [Indexed: 12/11/2022]
Abstract
There have been remarkable developments in the field of autoinflammatory diseases over the last 20 years. Research has led to definitions of new conditions, increased understanding of disease mechanisms and specific treatment. The polygenic autoinflammatory condition of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is the most common autoinflammatory disorder among children in many parts of the world. The clinical features often include clockwork regularity of episodes, prompt responses to corticosteroids and therapeutic effects of tonsillectomy, but the disease mechanisms are largely unknown. Conclusion This review discusses the emerging understanding of autoinflammatory diseases, with special emphasis on PFAPA.
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Affiliation(s)
- Per Wekell
- Department of Pediatrics NU‐Hospital Group Uddevalla Sweden
- Department of Pediatrics Institute of Clinical Sciences, University of Gothenburg Gothenburg Sweden
| | - Anna Karlsson
- Department of Rheumatology and Inflammation Research Institute of Medicine, University of Gothenburg Gothenburg Sweden
| | - Stefan Berg
- Department of Pediatrics Institute of Clinical Sciences, University of Gothenburg Gothenburg Sweden
- The Queen Silvia Children's Hospital Gothenburg Sweden
| | - Anders Fasth
- Department of Pediatrics Institute of Clinical Sciences, University of Gothenburg Gothenburg Sweden
- The Queen Silvia Children's Hospital Gothenburg Sweden
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Manthiram K, Nesbitt E, Morgan T, Edwards KM. Family History in Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. Pediatrics 2016; 138:peds.2015-4572. [PMID: 27565549 PMCID: PMC5005017 DOI: 10.1542/peds.2015-4572] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2016] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The goal of this study was to describe family history and inheritance patterns in patients with periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. METHODS We performed a case-control study to compare the family histories of patients with PFAPA recruited from Vanderbilt University Medical Center and matched healthy control subjects from a pediatric primary care practice in Nashville, Tennessee, by using a structured questionnaire. Characteristics of paired case subjects, control subjects, and their family members were compared by using McNemar's test and Wilcoxon signed-rank tests. RESULTS Eighty PFAPA index case subjects and 80 control subjects were recruited. Eighteen PFAPA case subjects (23%) had ≥1 family member with PFAPA. Parents of PFAPA index case subjects were more likely to have recurrent pharyngitis (36% vs 16%; P < .001) and recurrent aphthous stomatitis (46% vs 28%; P = .002) compared with parents of control subjects. Siblings of case subjects had a higher prevalence of PFAPA (10% vs 2%; P = .04), recurrent pharyngitis (24% vs 10%; P = .03), and recurrent aphthous stomatitis (27% vs 7%; P = .003) compared with siblings of control subjects. CONCLUSIONS A portion of PFAPA case subjects seems to be familial, implying an inherited genetic predisposition to the disorder and/or shared environmental exposures. First-degree relatives (parents and siblings) of patients with PFAPA have a higher prevalence of recurrent pharyngitis and aphthous stomatitis than relatives of control subjects, which suggests that these disorders represent reduced penetrance phenotypes of PFAPA. Further characterization of the genetics and inflammatory profiles of these patients and their relatives is warranted.
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Affiliation(s)
- Kalpana Manthiram
- Division of Pediatric Infectious Diseases, Department of Pediatrics, and
| | - Emily Nesbitt
- Division of Pediatric Infectious Diseases, Department of Pediatrics, and
| | - Thomas Morgan
- Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kathryn M. Edwards
- Division of Pediatric Infectious Diseases, Department of Pediatrics, and
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Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Joint Bone Spine 2016; 83:406-11. [DOI: 10.1016/j.jbspin.2015.08.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 08/27/2015] [Indexed: 11/17/2022]
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Tejesvi MV, Uhari M, Tapiainen T, Pirttilä AM, Suokas M, Lantto U, Koivunen P, Renko M. Tonsillar microbiota in children with PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome. Eur J Clin Microbiol Infect Dis 2016; 35:963-70. [PMID: 27025724 DOI: 10.1007/s10096-016-2623-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 03/09/2016] [Indexed: 01/12/2023]
Abstract
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a childhood febrile syndrome of unknown origin that is often cured with tonsillectomy. We aimed to compare the bacterial microbiota of the tonsils removed from PFAPA patients with those of controls. We used next-generation sequencing technology to investigate the bacterial microbiota of the tonsils of 30 PFAPA patients and 24 controls. We found significant differences in the presence and relative abundance of many bacteria between PFAPA cases and controls. For example, cyanobacteria, potential producers of microcystins and other toxins, were more common in the case samples (14/30, 47 %) than in the controls (4/24, 17 %, p = 0.02), and the mean relative abundance of cyanobacteria was higher in the case samples (0.2 %) than in the controls (0.01 %, p = 0.01). Streptococci were present in all samples in both groups, but their mean relative abundance was lower in the case samples (3.7 %) than in the controls (9.6 %, p = 0.01). Typical nasopharyngeal microbes such as fusobacteria, Prevotella, Tannerella, Porphyromonas, and Parvimonas dominated the microbiota of the tonsils in both groups. The microbiota of the tonsils removed from PFAPA patients differed significantly from those of the controls. Tonsillar microbiota may play a role in triggering the inflammatory processes that lead to symptoms of PFAPA.
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Affiliation(s)
- M V Tejesvi
- Genetics and Physiology, Faculty of Science, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
| | - M Uhari
- PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, 90029, Oulu, Finland
| | - T Tapiainen
- PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, 90029, Oulu, Finland
| | - A M Pirttilä
- Genetics and Physiology, Faculty of Science, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
| | - M Suokas
- Genetics and Physiology, Faculty of Science, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
| | - U Lantto
- PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland
- Department of Otorhinolaryngology, Oulu University Hospital, P.O. Box 23, 90029, Oulu, Finland
| | - P Koivunen
- PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland
- Department of Otorhinolaryngology, Oulu University Hospital, P.O. Box 23, 90029, Oulu, Finland
| | - M Renko
- PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
- Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, 90029, Oulu, Finland.
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Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis. Curr Rheumatol Rep 2016; 18:18. [DOI: 10.1007/s11926-016-0567-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Rigante D, Vitale A, Natale MF, Cantarini L. Lights and shadows in autoinflammatory syndromes from the childhood and adulthood perspective. Clin Rheumatol 2016; 35:565-572. [PMID: 26631101 DOI: 10.1007/s10067-015-3132-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/22/2015] [Indexed: 12/20/2022]
Abstract
In a high percentage of cases, the monogenic autoinflammatory syndromes (AIS), caused by subversion in the inflammasome homeostasis leading to cytokine oversecretion and characterized by multiple inflammatory pictures, start in childhood. However, the description of tardive manifestations, veiled phenotypes, and atypical clinical signs beginning in adulthood has been more and more reported in recent times, requiring that many specialists become confident with concepts, details, and management strategies of AIS. Differences between child- and adult-onset syndromes raise the question of whether pathogenic mechanisms might differ when the timetable of AIS onset diverges, but show that carefulness is needed to establish a straightforward diagnosis.
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Affiliation(s)
- Donato Rigante
- Institute of Pediatrics, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica Sacro Cuore, Rome, Italy
| | - Antonio Vitale
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 1, 53100, Siena, Italy
| | - Marco Francesco Natale
- Institute of Pediatrics, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica Sacro Cuore, Rome, Italy
| | - Luca Cantarini
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 1, 53100, Siena, Italy.
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Cantarini L, Vitale A, Bersani G, Nieves LM, Cattalini M, Lopalco G, Caso F, Costa L, Iannone F, Lapadula G, Galeazzi M, Ceribelli A, Brunetta E, Selmi C, Rigante D. PFAPA syndrome and Behçet's disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists. Clin Rheumatol 2016; 35:501-505. [PMID: 25665824 DOI: 10.1007/s10067-015-2890-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 12/30/2014] [Accepted: 01/26/2015] [Indexed: 12/14/2022]
Abstract
The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.
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Affiliation(s)
- Luca Cantarini
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
- Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, 53100, Siena, Italy.
| | - Antonio Vitale
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Giulia Bersani
- Institute of Pediatrics, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Laura Martin Nieves
- Rheumatology Service, Hospital Regional Universitario Carlos Haya, University of Màlaga, Màlaga, Spain
| | - Marco Cattalini
- Pediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy
| | - Giuseppe Lopalco
- Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinic Hospital, University of Bari, Bari, Italy
| | - Francesco Caso
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
| | - Luisa Costa
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Florenzo Iannone
- Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinic Hospital, University of Bari, Bari, Italy
| | - Giovanni Lapadula
- Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinic Hospital, University of Bari, Bari, Italy
| | - Mauro Galeazzi
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Angela Ceribelli
- Division of Rheumatology, Allergy, and Clinical Immunology, University of CA, Davis, CA, USA
| | - Enrico Brunetta
- Division of Rheumatology, Allergy, and Clinical Immunology, University of CA, Davis, CA, USA
| | - Carlo Selmi
- Division of Rheumatology, Allergy, and Clinical Immunology, University of CA, Davis, CA, USA
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Donato Rigante
- Institute of Pediatrics, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
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Pastore S, Vuch J, Bianco AM, Taddio A, Tommasini A. Fever tree revisited: From malaria to autoinflammatory diseases. World J Clin Pediatr 2015; 4:106-112. [PMID: 26566482 PMCID: PMC4637800 DOI: 10.5409/wjcp.v4.i4.106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 03/20/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.
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Lantto U, Koivunen P, Tapiainen T, Glumoff V, Hirvikoski P, Uhari M, Renko M. Microbes of the tonsils in PFAPA (Periodic Fever, Aphtous stomatitis, Pharyngitis and Adenitis) syndrome - a possible trigger of febrile episodes. APMIS 2015; 123:523-9. [DOI: 10.1111/apm.12383] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/12/2015] [Indexed: 12/15/2022]
Affiliation(s)
- Ulla Lantto
- Department of Otorhinolaryngology; Oulu University Hospital and Institute of Clinical Medicine; University of Oulu; Oulu Finland
| | - Petri Koivunen
- Department of Otorhinolaryngology; Oulu University Hospital and Institute of Clinical Medicine; University of Oulu; Oulu Finland
| | - Terhi Tapiainen
- Department of Pediatrics; Oulu University Hospital and Medical Research Center; University of Oulu; Oulu Finland
| | - Virpi Glumoff
- Institute of Diagnostics; Department of Medical Microbiology and Immunology; University of Oulu; Oulu Finland
| | - Pasi Hirvikoski
- Department of Pathology; Oulu University Hospital; Oulu Finland
| | - Matti Uhari
- Department of Pediatrics; Oulu University Hospital and Medical Research Center; University of Oulu; Oulu Finland
| | - Marjo Renko
- Department of Pediatrics; Oulu University Hospital and Medical Research Center; University of Oulu; Oulu Finland
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Cantarini L, Vitale A, Lucherini OM, De Clemente C, Caso F, Costa L, Emmi G, Silvestri E, Magnotti F, Maggio MC, Prinzi E, Lopalco G, Frediani B, Cimaz R, Galeazzi M, Rigante D. The labyrinth of autoinflammatory disorders: a snapshot on the activity of a third-level center in Italy. Clin Rheumatol 2015; 34:17-28. [PMID: 24953660 DOI: 10.1007/s10067-014-2721-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 06/06/2014] [Indexed: 12/14/2022]
Abstract
Autoinflammatory disorders (AIDs) are a novel class of diseases elicited by mutations in genes regulating the homeostasis of innate immune complexes, named inflammasomes, which lead to uncontrolled oversecretion of the proinflammatory cytokine interleukin-1β. Protean inflammatory symptoms are variably associated with periodic fever, depicting multiple specific conditions. Childhood is usually the lifetime in which most hereditary AIDs start, though still a relevant number of patients may experience a delayed disease onset and receive a definite diagnosis during adulthood. As a major referral laboratory for patients with recurrent fevers, we have tested samples from 787 patients in the period September 2007-March 2014, with a total of 1,328 AID-related genes evaluated and a gene/patient ratio of 1.69. In this report, we describe our experience in the clinical approach to AIDs, highlight the most striking differences between child and adult-onset AIDs, and shed an eye-opening insight into their diagnostic process.
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Affiliation(s)
- Luca Cantarini
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy,
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Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev 2014:CD008669. [PMID: 25209127 DOI: 10.1002/14651858.cd008669.pub2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane review first published in 2010. OBJECTIVES To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) in children with PFAPA. SEARCH METHODS We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2013. SELECTION CRITERIA Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted data. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias.One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months.Combining the trial results suggests that patients with PFAPA experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution).There was a large overall reduction in the average number of episodes over the total length of follow-up in these studies (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years. The severity, as indicated by the length of PFAPA symptoms during these episodes, was also reduced. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group. The proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92).Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Other outcomes such as quality of life, number of days with pain after surgery and absence from school were not measured or reported. AUTHORS' CONCLUSIONS The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.
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Affiliation(s)
- Martin J Burton
- UK Cochrane Centre, Summertown Pavilion, 18 - 24 Middle Way, Oxford, UK, OX2 7LG
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Ortega N, Berenguer M, Garre A, Molina M. Síndrome PFAPA del adulto. Rev Clin Esp 2014; 214:351-2. [DOI: 10.1016/j.rce.2014.03.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 02/20/2014] [Accepted: 03/27/2014] [Indexed: 10/25/2022]
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Esposito S, Bianchini S, Fattizzo M, Baggi E, Marchisio P, Rigante D. The enigma of periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Pediatr Infect Dis J 2014; 33:650-652. [PMID: 24642520 DOI: 10.1097/inf.0000000000000346] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Susanna Esposito
- From the *Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; and †Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy
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Stagi S, Bertini F, Rigante D, Falcini F. Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Int J Pediatr Otorhinolaryngol 2014; 78:964-968. [PMID: 24746456 DOI: 10.1016/j.ijporl.2014.03.026] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 03/20/2014] [Accepted: 03/21/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease characterized by regularly recurrent fever episodes due to seemingly unprovoked inflammation. OBJECTIVE To assess serum 25-hydroxyvitamin D [25(OH)D] concentrations in children with PFAPA syndrome and evaluate longitudinally the effect of wintertime vitamin D supplementation on the disease course. STUDY DESIGN We have evaluated 25 Italian patients (19 males, 6 females, aged 2.4-5.3 years), fulfilling the Euro-Fever PFAPA criteria. For each patient, we recorded demographic and anthropometric data, clinical manifestations, serum calcium, phosphate, and 25(OH)D. After 400 IU vitamin D supplementation during wintertime, clinical and auxological characteristics, calcium, phosphate, and 25(OH)D levels were re-evaluated. Data were compared with a sex- and age-matched control group. RESULTS PFAPA patients showed reduced 25(OH)D levels than controls (p<0.0001). Regarding the effect of seasons on vitamin D, winter 25(OH)D levels were significantly reduced than summer ones (p<0.005). Moreover, these levels were significantly lower than in healthy controls (p<0.005), and correlated with both fever episodes (p<0.005) and C-reactive protein values (p<0.005). After vitamin D supplementation, PFAPA patients showed a significantly decreased number of febrile episodes and modification of their characteristics (mean duration of fever episodes, p<0.05; number of febrile episodes per year p<0.005). CONCLUSIONS Deficient and insufficient vitamin D serum levels were found in most children with PFAPA syndrome, and hypovitaminosis D might be a significant risk factor for PFAPA flares. However, vitamin D supplementation seems to significantly reduce the typical PFAPA episodes and their duration, supporting the role of vitamin D as an immune-regulatory factor in this syndrome.
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Affiliation(s)
- Stefano Stagi
- Health's Sciences Department, University of Florence, Anna Meyer Children's University Hospital, Florence, Italy.
| | - Federico Bertini
- Department of BioMedicine, Section of Rheumatology, Transition Clinic, University of Florence, Florence, Italy
| | - Donato Rigante
- Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy
| | - Fernanda Falcini
- Department of BioMedicine, Section of Rheumatology, Transition Clinic, University of Florence, Florence, Italy
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Tekin M, Toplu Y, Kahramaner Z, Erdemir A, Gulyuz A, Konca C, Uckardes F. The mean platelet volume levels in children with PFAPA syndrome. Int J Pediatr Otorhinolaryngol 2014; 78:850-3. [PMID: 24656227 DOI: 10.1016/j.ijporl.2014.02.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 02/20/2014] [Accepted: 02/21/2014] [Indexed: 01/06/2023]
Abstract
OBJECTIVES To 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. METHODS The 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. RESULTS The 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. CONCLUSIONS The 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.
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Affiliation(s)
- Mehmet Tekin
- Adiyaman University, School of Medicine, Department of Pediatrics, Adiyaman, Turkey.
| | - Yuksel Toplu
- Inonu University, Medical Faculty, Department of Otorhinolaryngology, Malatya, Turkey
| | - Zelal Kahramaner
- Adiyaman University, School of Medicine, Department of Pediatrics, Adiyaman, Turkey; Adiyaman University, School of Medicine, Department of Pediatrics, Neonatology Clinic, Adiyaman, Turkey
| | - Aydin Erdemir
- Adiyaman University, School of Medicine, Department of Pediatrics, Adiyaman, Turkey; Adiyaman University, School of Medicine, Department of Pediatrics, Neonatology Clinic, Adiyaman, Turkey
| | | | - Capan Konca
- Adiyaman University, School of Medicine, Department of Pediatrics, Adiyaman, Turkey
| | - Fatih Uckardes
- Adiyaman University, School of Medicine, Department of Statistics, Adiyaman, Turkey
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