International journal of pediatric otorhinolaryngology •
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 regarding the immunological role of the tonsils in the PFAPA syndrome. We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0-18 years with PFAPA. Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease.
Førsvoll J, Janssen EA, Møller I, Wathne N, Skaland I , et al.
Scandinavian journal of immunology •
The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is an autoinflammatory disorder of unknown aetiology. Tonsillectomy may cause a prompt resolution of the syndrome. The aim was to study the histologic and immunological aspects of the palatine tonsils in PFAPA, to help understand the pathophysiology of the syndrome. Tonsils from children with PFAPA (n = 11) and children with tonsillar hypertrophy (n = 16) were evaluated histologically after haematoxylin and eosin staining. The number of different cell types was identified immunohistochemically by cluster of differentiation (CD) markers: CD3 (T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), CD15 (neutrophils), CD20 (B cells), CD45 (all leucocytes), CD57 (NK cells) and CD163 (monocytes and macrophages). Tonsils from children with PFAPA showed reactive lymphoid hyperplasia dominated by well-developed germinal centres with many tingible body macrophages. The histologic findings were unspecific, and a similar morphologic appearance was also found in the tonsils from controls. The number of CD8+ cells in germinal centres differed between children with PFAPA [median 9 cells (quartiles: 5, 15)] and controls [18 cells (12, 33) (P = 0.001)] and between children with PFAPA with (median 14 cells; 9, 16) and without (4 cells; 3, 8) aphthous stomatitis (P = 0.015). For the other cell types, no differences in germinal centres were found between children with PFAPA and controls. In conclusion, a lower number of CD8+ cells were found in germinal centres of tonsils in children with PFAPA compared to controls, which may be a feature linked to the aetiology of the syndrome.
The Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) is the most common periodic fever syndrome in childhood. Clinically, PFAPA may resemble autoinflammatory diseases, but the etiology is not fully understood. We measured inflammatory proteins in plasma and hematologic parameters in children with PFAPA during and between febrile episodes, and in a control group with suspected bacterial pneumonia. In children with PFAPA, a first blood sample was taken within 24 hours of a febrile episode and a second sample between episodes. In children with pneumonia, the first sample was taken shortly after admission and a second sample after full recovery. A total of 22 children with PFAPA and 14 children with pneumonia were included. In children with PFAPA, levels of interleukin (IL) 6, CXCL10 and CCL4 were significantly increased during febrile episodes. The levels of IL-6 and CXCL10 were higher in children with PFAPA during febrile episodes than in children with pneumonia. The levels of CXCL10 remained higher in children with PFAPA between febrile episodes compared to children with pneumonia after recovery. Children with PFAPA had a relative eosinopenia and lymphocytopenia with reduced numbers of both CD4+ and CD8+ T cells during febrile episodes. This pattern was not observed in the children with pneumonia. The results indicate an innate immune response as the initial step in PFAPA, and a subsequent adaptive response with activation and redistribution of T cells. Moreover, an activation of the innate immune system involving CXCL10 may persist between febrile episodes. CXCL10 may be a possibly clinical marker in children with PFAPA.
To describe the incidence, epidemiology, clinical presentation and clinical outcome of children with the syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) in a population-based study. In a prospective population-based study, all children in South Rogaland, Norway, diagnosed with PFAPA during 2004-2010 were evaluated clinically, and parents were interviewed systematically. A follow-up interview was performed for all patients. A total of 46 children (32 boys; p = 0.011) were diagnosed with PFAPA. We calculated an incidence of 2.3 per 10 000 children up to 5 years of age. The median age of onset was 11.0 months (quartiles: 5.0, 14.8). Nearly 37 children were followed until resolution. In 17 of these, a tonsillectomy was performed with prompt resolution of PFAPA in all. The median age of spontaneous resolution was 60.2 months (range 24-120) and in children with tonsillectomy 50.9 months (range 15-128). The incidence of PFAPA was 2.3 per 10 000 children up to 5 years of age. In the majority of cases, onset of symptoms may be during the first year of life.
Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke •
In children with recurrent episodes of fever, the cause may be the periodic fever syndrome (PFAPA-syndrome). The condition is not uncommon, and awareness of the syndrome is important for avoiding unnecessary investigations and treatment. The article presents an overview of the PFAPA-syndrome. The overview was based on Pubmed and Medline searches and data from 22 children with PFAPA-syndrome diagnosed at Stavanger University Hospital. In children with PFAPA-syndrome the fever occurs regularly, appears abruptly and lasts for three to five days. Typical symptoms are cervical adenitis, tonsillitis/pharyngitis or aphthous stomatitis, often accompanied by headache, abdominal pain, nausea and reduced general condition. Of the 22 children, 17 were boys. The median age of debut was 12 months, median duration of fever four days, and median time between episodes 25 days. The most common symptoms were cervical adenitis (n = 18) and tonsillitis/pharyngitis (n = 16). During episodes, all children had high fever, reduced general condition, no proved infection but typical high levels of C-reactive protein. More than half of the children had been given antibiotics on at least five occasions before the diagnosis of PFAPA-syndrome. With a typical history and clinical investigation, the need for further investigations is limited. The diagnosis must be considered in children younger than five years of age with periodic fever without signs of airway infection. When PFAPA-syndrome is suspected, the child should be referred to a paediatrician. There is no evidence-based treatment for PFAPA-syndrome, but tonsillectomy is considered to have an effect.