Vyzhga Y, Wittkowski H, Hentgen V, Georgin-Lavialle S, Theodoropoulou A , et al.
Pediatric rheumatology online journal •
Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.
Gerritsma AM, Sutera D, Cantarini L, Cattalini M, Lachmann HJ , et al.
Clinical and experimental rheumatology •
To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
Vanoni F, Caorsi R, Aeby S, Cochard M, Antón J , et al.
Pediatric rheumatology online journal •
Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far. A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance. The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients. Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.
GMS current topics in otorhinolaryngology, head and neck surgery •
Surgery of the tonsils is still one of the most frequent procedures during childhood. Due to a series of fatal outcomes after hemorrhage in children in Austria in 2006, the standards and indications for tonsillectomy have slowly changed in Germany. However, no national guidelines exist and the frequency of tonsil surgery varies across the country. In some districts eight times more children were tonsillectomized than in others. A tonsillectomy in children under six years should only be done if the child suffers from recurrent acute bacterially tonsillitis. In all other cases (i.e. hyperplasia of the tonsils) the low risk partial tonsillectomy should be the first line therapy. Postoperative pain and the risk of hemorrhage are much lower in partial tonsillectomy (=tonsillotomy). No matter whether the tonsillotomy is done by laser, radiofrequency, shaver, coblation, bipolar scissor or Colorado needle, as long as the crypts are kept open and some tonsil tissue is left behind. Total extracapsular tonsillectomy is still indicated in severely affected children with recurrent infections of the tonsils, allergy to antibiotics, PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) and peritonsillar abscess. With regard to the frequency and seriousness of the recurrent tonsillitis the indication for tonsillectomy in children is justified if 7 or more well-documented, clinically important, adequately treated episodes of throat infection occur in the preceding year, or 5 or more of such episodes occur in each of the 2 preceding years (according to the paradise criteria). Diagnosis of acute tonsillitis is clinical, but sometimes it is hard to distinguish viral from bacterial infections. Rapid antigen testing has a very low sensitivity in the diagnosis of bacterial tonsillitis and swabs are highly sensitive but take a long time. In all microbiological tests the treating physician has to keep in mind, that most of the bacterials, viruses and fungi belong to the healthy flora and do no harm. Ten percent of healthy children even bear strepptococcus pyogenes all the time in the tonsils with no clinical signs. In these children decolonization is not necessary. Therefore, microbiological screening tests in children without symptoms are senseless and do not justify an antibiotic treatment (which is sometimes postulated by the kindergartens). The acute tonsillitis should be treated with steroids (e.g. dexamethasone), NSAIDs (e.g. ibuprofene) and betalactam antibiotics (e.g. penicillin or cefuroxime). With respect to the symptom reduction and primary healing the short-term late-generation antibiotic therapy (azithromycin, clarithromycin or cephalosporine for three to five days) is comparable to the long-term penicilline therapy. There is no difference in the course of healing, recurrence or microbiological resistance between the short-term penicilline therapy and the standard ten days therapy. On the other hand, only the ten days antibiotic therapy has proven to be effective in the prevention of rheumatic fever and glomerulonephritic diseases. The incidence of rheumatic heart disease is currently 0.5 per 100,000 children of school age. The main morbidity after tonsillectomy is pain and the late haemorrhage. Posttonsillectomy bleeding can occur till the whole wound is completely healed, which is normally after three weeks. Life-threatening haemorrhages occur often after smaller bleedings, which can spontaneously cease. That is why every haemorrhage, even the smallest, has to be treated properly and in ward. Patients and parents have to be informed about the correct behaviour in case of haemorrhage with a written consent before the surgery. The handout should contain important addresses, phone numbers and contact persons. Almost all cases of fatal outcome after tonsillectomy were due to false management of haemorrhage. Haemorrhage in small children can be especially life-threatening because of the lower blood volume and the danger of aspiration with asphyxia. A massive haemorrhage is an extreme challenge for every paramedic or emergency doctor because of the difficult airway management. Intubation is only possible with appropriate inflexible suction tubes. All different surgical techniques have the risk of haemorrhage and even the best surgeon will experience a postoperative haemorrhage. The lowest risk of haemorrhage is after cold dissection with ligature or suturing. All "hot" techniques with laser, radiofrequency, coblation, mono- or bipolar forceps have a higher risk of late haemorrhage. Children with a hereditary coagulopathy have a higher risk of haemorrhage. It is possible, that these children were not identified before surgery. Therefore it is recommended by the Society of paediatrics, anaesthesia and ENT, that a standardised questionnaire should be answered by the parents before tonsillectomy and adenoidectomy. This 17-point-checklist questionnaire is more sensitive and easier to perform than a screening with blood tests (e.g. INR and PTT). Unfortunately, a lot of surgeons still screen the children preoperatively by coagulative blood tests, although these tests are inappropriate and incapable of detecting the von Willebrand disease, which is the most frequent coagulopathy in Europe. The preoperative information about the surgery should be done with the child and the parents in a calm and objective atmosphere with a written consent. A copy of the consent with the signature of the surgeon and both custodial parents has to be handed out to the parents.
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG •
Autoinflammatory diseases encompass a group of inflammatory diseases that are non-infectious, non-allergic, non-autoimmune and non-immunodeficient. The term was initially coined for a small group of familial periodic fever syndromes of which familial Mediterranean fever (FMF) is the most common and best known. Genetic and molecular analyses demonstrated for the majority of these diseases an impairment of inflammasomes to cause an increased activity of an interleukin-1-dependent inflammatory response. Over the last years an increasing number of either rare hereditary syndromes or acquired common diseases could be summarized under the designation of autoinflammatory disease, thus creating an emerging new rubric of inflammatory diseases. Many of them display cutaneous manifestations as both concomitant or more rarely main symptoms. To name some of them like erysipelas-like erythema in FMF; urticaria-like rashes in tumor necrosis factor receptor 1- or cryopyrin-associated periodic syndromes (TRAPS, CAPS), hyperimmunoglobulin D syndrome (HIDS) or Schnitzler syndrome; pyoderma gangrenosum and acne in PAPA syndrome; or behçetoid aphthous ulcerations in HIDS and PFAPA syndrome. Based on the new insights into pathogenesis one increasingly realizes the good response of these diseases to IL-1 antagonist therapies.
Proceedings of the National Academy of Sciences of the United States of America •
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
Stojanov S, Hoffmann F, Kéry A, Renner ED, Hartl D , et al.
European cytokine network •
PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response.