Acute Aseptic Meningitis Temporally Associated with Intravenous Polyclonal Immunoglobulin Therapy: A Systematic Review.

An acute aseptic meningitis has been occasionally observed on intravenous polyclonal human immunoglobulin therapy. Since case reports cannot be employed to draw inferences about the relationships between immunoglobulin therapy and meningitis, we conducted a systematic review and meta-analysis of the literature. Eligible were cases, case series, and pharmacovigilance studies. We found 71 individually documented cases (36 individuals ≤ 18 years of age) of meningitis. Ninety percent of cases presented ≤ 3 days after initiating immunoglobulin therapy and recovered within ≤ 7 days (with a shorter disease duration in children: ≤ 3 days in 29 (94%) cases). In 22 (31%) instances, the authors noted a link between the onset of meningitis and a rapid intravenous infusion of immunoglobulins. Cerebrospinal fluid analysis revealed a predominantly neutrophilic (N = 46, 66%) pleocytosis. Recurrences after re-exposure were observed in eight (N = 11%) patients. Eight case series addressed the prevalence of meningitis in 4089 patients treated with immunoglobulins. A pooled prevalence of 0.6% was noted. Finally, pharmacovigilance data revealed that meningitis temporally associated with intravenous immunoglobulin therapy occurred with at least five different products. In conclusion, intravenous immunoglobulin may cause an acute aseptic meningitis. The clinical features remit rapidly after discontinuing the medication.

Increased breadth and neutralization of antibodies against SARS-CoV-2 variants after infection and vaccination: A serosurveillance study in pediatric patients of Southern Switzerland.

Little information is available about the nature of the immune response in children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. The aim of this study is to define the seroprevalence and the features of the antibody response in children of Southern Switzerland during the different waves of Coronavirus Disease 2019 (COVID-19) pandemic. By analyzing 756 sera collected from children aged 0 to 16 years admitted to the Institute of Pediatrics of Southern Switzerland during the prepandemic period (before March 2020) and the first four pandemic waves (between March 2020 and June 2022), we investigated binding titers, cross-reactivity, and neutralizing properties of the serum antibodies against SARS-CoV-2 variants. Seroprevalence varied from 6% during the first wave to 14% and 17% during the second and third waves, respectively, peaking at 39% during the fourth wave. The 96 seropositive cases were mostly asymptomatic (42.7%) or showed mild (20.8%) to moderate (32.3%) symptoms. Moderate symptoms and close contact with COVID-19-positive individuals were associated with a higher infection risk (P < 0.001). The antibody response was mainly driven by IgG directed to the receptor-binding domain (RBD) of Wuhan-1 SARS-CoV-2 Spike (S). Children infected in the first three waves produced antibodies with up to 11-fold and 5.5-fold reduction in binding and neutralizing titers, respectively, against different SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, BA.2, and BA.5. Such reductions were less pronounced in children infected during the fourth wave, who showed the highest frequency and titers of neutralizing antibodies against the same variants. Compared to infection, vaccination with a Wuhan-1-based messenger RNA (mRNA) vaccine induced higher and heterogenous levels of antibodies cross-reacting to the different SARS-CoV-2 variants analyzed.   Conclusions: Despite the high burden of COVID-19 in Southern Switzerland, we observed an initial low seroprevalence of SARS-CoV-2 in children, which increased in the later waves. The antibody response was poor in the first three waves and improved in the fourth wave, when children produced higher levels of neutralizing antibodies after vaccination or infection with Delta and/or Omicron variants. What is Known: • Children were marginally affected by the initial SARS-CoV-2 variants. • The number of infected and hospitalized children increased after the appearance of the Omicron variants. What is New: • Seroprevalence of SARS-CoV-2 in children of Southern Switzerland increased overtime. • Children produced higher levels of neutralizing antibodies after vaccination or infection with Delta and/or Omicron variants in the fourth wave compared to children infected in the first three waves.

Individual and environmental determinants associated with longer times to access pediatric rheumatology centers for patients with juvenile idiopathic arthritis, a JIR cohort study.

BACKGROUND: Despite guidelines, poor access to appropriate care for juvenile idiopathic arthritis (JIA) patients remains a global issue. Prompt referral to a pediatric rheumatology (PR) center and effective care is known to be critical for changing the natural history of the disease and improving long-term prognosis. This project assesses socio-economic factors of delayed referral to a pediatric rheumatologist (PRst) for JIA patients in France and Switzerland within the Juvenile Inflammatory Rheumatism (JIR) Cohort. METHODS: All patients diagnosed with JIA, presenting at one center of the JIRcohort in France or Switzerland with additional data on referral pathway were included. Patient characteristics at first visit to the PR center, dates of visits to healthcare providers during referral, and parent characteristics were extracted from the JIRcohort database. RESULTS: Two hundred fifty children were included. The overall median time to first PR assessment was 2.4 months [1.3; 6.9] and ranged widely across the JIA subtypes, from 1.4 months [0.6; 3.8] for children with systemic juvenile idiopathic arthritis (sJIA) to 5.3 months [2.0; 19.1] for children with enthesitis-related arthritis (ERA). A diagnosis of ERA and an appointment with an orthopedist during the referral pathway were significantly associated with a longer time before the first PR visit (hazard ratio HR 0.50 [95% CI: 0.29; 0.84]) and HR 0.68 [95% CI: 0.49; 0.93], respectively) in multivariable analysis. Having a mother with a post-graduate educational attainment level was tendentially associated with a shorter time before the first PR visit, (HR 1.32 [95% CI: 0.99; 1.78]). CONCLUSIONS: Time to first PRst visit was most often short compared to other studies and close to the British recommendations. However, this time remained too long for many patients. We observed no social inequities in access to a PRst, but we show the need to improve effective pathway and access to a PR center for JIA patients.

Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial.

BACKGROUND: The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS: This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS: Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log10 transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION: In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING: NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.

Autoimmune markers and vascular immune deposits in Finkelstein-Seidlmayer vasculitis: Systematic literature review.

Finkelstein-Seidlmayer vasculitis, also called acute hemorrhagic edema of young children or infantile immunoglobulin A vasculitis, is habitually a benign skin-limited small vessel leukocytoclastic vasculitis that mainly affects infants 24 months or less of age. Since this disease is commonly triggered by an infection, an immune-mediated origin has been postulated. To better appreciate the possible underlying immune mechanism of this vasculitis, we addressed circulating autoimmune markers and vascular immune deposits in patients contained in the Acute Hemorrhagic Edema BIbliographic Database, which incorporates all original reports on Finkelstein-Seidlmayer vasculitis. A test for at least one circulating autoimmune marker or a vascular immune deposit was performed in 243 cases. Subunits of complement system C4 resulted pathologically reduced in 4.7% and C3 in 1.4%, rheumatoid factor was detected in 6.1%, and antinuclear antibodies in 1.9% of cases. Antineutrophil cytoplasmic antibodies were never demonstrated. Immunofluorescence studies were performed on 125 skin biopsy specimens and resulted positive for complement subunits in 46%, fibrinogen in 45%, immunoglobulin A in 25%, immunoglobulin M in 24%, immunoglobulin G in 13%, and immunoglobulin E in 4.2% of cases. Infants testing positive for vascular immunoglobulin A deposits did not present a higher prevalence of systemic involvement or recurrences, nor a longer disease duration. In conclusion, we detected a very low prevalence of circulating autoimmune marker positivity in Finkelstein-Seidlmayer patients. Available immunofluorescence data support the notion that immune factors play a relevant role in this vasculitis. Furthermore, vascular immunoglobulin A deposits seem not to play a crucial role in this disease.

Multicenter Randomized Trial of Methylprednisolone vs. Intravenous Immunoglobulins to Treat the Pediatric Inflammatory Multisystem Syndrome-Temporally Associated With SARS-CoV-2 (PIMS-TS): Protocol of the Swissped RECOVERY Trial.

Introduction: In 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG. Methods and Analysis: Swissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents <18 years hospitalized with a diagnosis of PIMS-TS. The trial is recruiting at 10 sites across Switzerland. Patients diagnosed with PIMS-TS are randomized 1:1 to methylprednisolone IV (10 mg/kg/day for 3 days) or IVIG (2 g/kg as a single dose). The primary outcome is hospital length of stay censored at day 28, death, or discharge (whichever is first). The target total sample size is ~80 patients 1:1 randomized to each study arm. Ancillary and exploratory studies on inflammation, vaccination acceptance and coverage, long-term outcomes, and healthcare costs are pre-planned. Significance: Currently, robust trial evidence for the treatment of PIMS-TS is lacking, with a controversy surrounding the use of corticosteroids vs. IVIG. This trial will provide evidence for the effectiveness and safety of these two treatments. Ethics and Dissemination: The study protocol, which was designed based on the U.K. RECOVERY trial, the patient information and consent forms, and other study-specific study documents were approved by the local ethics committees (Project ID: 2021-00362). Registration Details: The study is registered on the Swiss National Clinical Trials Portal (SNCTP000004720) and Clinicaltrials.gov (NCT04826588).

Skin Eruptions in Acute Hemorrhagic Edema of Young Children: Systematic Review of the Literature.

BACKGROUND: Acute hemorrhagic edema is a skin-limited small-vessel leukocytoclastic vasculitis, which affects infants 4 weeks to 2 years of age and remits within 3 weeks. The diagnosis is made clinically in not-ill appearing children with acute onset of raised annular or nummular eruptions and edema. In this vasculitis, type, distribution, and evolution of the rash have never been systemically investigated. To address this issue, we employed the data contained in the Acute Hemorrhagic Edema Bibliographic Database, which incorporates all reports on acute hemorrhagic edema. SUMMARY: Key features of rash were documented in 383 children. Annular eruptions in a strict sense, usually targetoid, were reported in 375 (98%) cases (many children also presented polycyclic or arciform eruptions). Nummular eruptions were also very common (n = 358; 93%). Purpuric eruptions and ecchymoses were reported in the vast majority of cases. Macules and wheals were described in a minority of cases. Edema, detected in all cases, was mostly painful, indurated and nonpitting. The following regions were affected, in decreasing order, by annular or nummular eruptions: legs, feet, face, arms, ears, trunk, and genitals. With the exception of feet, which were very often affected, the same distribution was reported for edema. The initial eruption was often a wheal or a macule that evolved into a nummular or an annular eruption. Nummular eruptions successively evolved into annular ones. KEY MESSAGE: This study carefully characterizes type, distribution, and evolution of skin eruption in acute hemorrhagic edema. The data help physicians to rapidly and noninvasively make the clinical diagnosis of this vasculitis.

Tubulointerstitial nephritis and uveitis syndrome: a systematic review.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is defined as the occurrence of tubulointerstitial nephritis (TIN) and uveitis in the absence of other systemic diseases. The most comprehensive review on this condition was published in 2001. METHODS: We conducted a systematic review of the literature for cases of TINU syndrome. MEDLINE and Embase databases were screened. Full-length articles or letters reporting cases with both TIN and uveitis were selected. We investigated differences between males and females and paediatric and adult cases. Multivariate analysis was performed to identify potential risk factors for chronic kidney disease (CKD) development. RESULTS: A total of 233 articles reporting 592 TINU cases were retained for the analysis. The median age of the included subjects was 17 years (interquartile range 13-46) with a female predominance (65%). Uveitis most frequently (52%) followed renal disease and was mostly anterior (65%) and bilateral (88%). Children tended to have more ocular relapses, while they were slightly less likely than adults to suffer from acute kidney injury and to develop CKD. Adult age as well as posterior or panuveitis were associated with an increased risk of developing CKD. CONCLUSIONS: TINU affects both children and adults, with some differences between these two categories. Adult age and the presence of a posterior uveitis or panuveitis appear to be associated with the development of CKD.

Current practice of transitional care for adolescents and young adults in Swiss paediatric and adult rheumatology centres.

BACKGROUND: About half of all children with rheumatic diseases need continuous medical care during adolescence and adulthood. A good transition into adult rheumatology is essential. Guidelines for a structured transition process have therefore been recommended by the European League Against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PReS). However, implementation of these guidelines requires resources often not available in a busy clinical practice. AIMS: To assess the current practice of transitional care in Switzerland in relation to EULAR/PReS recommendations and to describe gaps and challenges in following the recommendations. METHODS: All paediatric Swiss rheumatology centres and their collaborating adult centres offering a transition service to adult care were invited to participate in this survey. The responsible paediatric and adult rheumatologist of each centre was interviewed separately using a structured manual addressing the EULAR/PReS transitional care recommendations. RESULTS: All 10 paediatric and 9 out of 10 adult rheumatologists agreed to participate. Centres varied in the number of patients in transition, from n = 0 to n = 111. The following EULAR/PReS recommendations were implemented and applied in most centres: continuity in the healthcare team, consultations focused on adolescents and young adults, joint consultations between the paediatric and adult rheumatologist, and access to the EULAR website. Only rarely did a centre have a written transition policy or evaluate their transitional care programme. The vast majority of the interviewees had no specific training in adolescent health. Most centres rated their transitional care performance as very good. CONCLUSION: Transition in Switzerland is not uniform and consequently the implementation of the EULAR/PReS recommendations is variable in Swiss rheumatology centres. Skills of healthcare professionals, continuity between clinical settings, size of the centres, and hospital focus on the needs of adolescents and young adults may represent key predictors of successful transitional care for patients with chronic rheumatic diseases. Future studies should examine these variables.

Skin and Mucous Membrane Eruptions Associated with Chlamydophila Pneumoniae Respiratory Infections: Literature Review.

BACKGROUND: Mycoplasma pneumoniae pneumonia is sometimes associated with skin or mucous membrane eruptions. Available reviews do not address the association of Chlamydophila pneumoniae pneumonia with skin eruptions. We therefore conducted a systematic review of the literature addressing this issue. The National Library of Medicine, Excerpta Medica, and Web of Science databases were employed. SUMMARY: In two reports, skin lesions and especially urticaria were more common (p < 0.05) in atypical pneumonia caused by C. pneumoniae as compared with M. pneumoniae. We found 47 patients (<18 years, n = 16; ≥18 years, n = 31) affected by a C. pneumoniae atypical pneumonia, which was associated with erythema nodosum, erythema multiforme minus, erythema multiforme majus, isolated mucositis, or cutaneous vasculitis. We also found the case of a boy with C. pneumoniae pneumonia and acute generalized exanthematous pustulosis. We did not find any case of C. pneumoniae respiratory infection associated with either Gianotti-Crosti syndrome, pityriasis lichenoides et varioliformis acuta Mucha-Habermann, or varicella-like skin eruptions.

Increased Prevalence of NLRP3 Q703K Variant Among Patients With Autoinflammatory Diseases: An International Multicentric Study.

Background: The NLRP3 inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of NLRP3 gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of NLRP3, that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. Objectives: We aimed to investigate the potential genetic impact of the NLRP3 variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). Methods: This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K NLRP3 variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. Results: We report 42 patients with the Q703K NLRP3 genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The in vitro production of IL-1ß was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. Conclusion: The evidence we report in our study shows an increased prevalence of NLRP3 Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.

Nicolau syndrome caused by non-steroidal anti-inflammatory drugs: Systematic literature review.

AIM: Intramuscular or, more rarely, local drug injection is occasionally followed by immediate local pain, livedoid skin lesions and, some days later, the development of ischemic lesions. This very uncommon but potentially severe reaction, termed Nicolau syndrome, is traditionally associated with bismuth and ß-lactam antimicrobials. The aim of this report was to review the literature associating Nicolau syndrome with the administration of non-steroidal anti-inflammatory drugs. METHODS: The National Library, Excerpta Medica, Web of Science and Cochrane library databases were used. RESULTS: Sixty-two cases (40 females and 22 males aged from 13 to 81, median 57 years) of Nicolau syndrome were published after 1992. Fifty-three cases occurred after diclofenac. The remaining nine cases were associated with ketoprofen (N = 2), ketorolac (N = 2), phenylbutazone (N = 2), etofenamate (N = 1), ibuprofen (N = 1) and piroxicam (N = 1). CONCLUSION: Although Nicolau syndrome is extremely uncommon, physicians must be aware of this complication after intramuscular administration of non-steroidal anti-inflammatory drugs and should avoid unnecessary injections.

A Systematic Review of Clinical Practice Guidelines for Acute Procedural Pain on Neonates.

OBJECTIVES: During hospitalization in neonatal intensive care units, neonates are exposed to many painful procedures within a stressful environment. To date, many evidence-based guidelines are available. However, the quality of these guidelines and their clinical application remain unclear. This systematic review aimed to determinie the quality of existing guidelines on the management of procedural pain in neonates and to summarize the recommendations provided by these guidelines. MATERIALS AND METHODS: A structured search was conducted in Embase, PubMed, CINAHL, JBI database, and gray literature resources in November 2018 to identify relevant guidelines published from 2007 onward. Published guidelines and guidelines from complementary searches were included in the treating assessment or management of procedural pain in neonates. The methodological quality was analyzed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. RESULTS: A total of 1154 records were identified. After screening for eligibility, 17 guidelines were included in this review. Among these, 11 were identified to be high-quality guidelines. Besides the usual recommendations for pharmacological and nonpharmacological treatments, the inclusion of parents, improving interprofessional collaboration, and considering the setting were identified as important elements. DISCUSSION: The results of this review show that there is a need to improve the methodological quality of guidelines for procedural pain in newborns. The set of recommendations for procedural pain prevention needs to involve not only pharmacological and nonpharmacological pain treatment but also parents and interprofessional collaboration. It is also essential to take into account facilitators, barriers, and the context to improve pain management.

Immune deposits in skin vessels of patients with acute hemorrhagic edema of young children: A systematic literature review.

BACKGROUND: Acute hemorrhagic edema of young children is a benign skin-limited vasculitis mainly affecting children 2 to 24 months of age, which is often considered the infantile variant of immunoglobulin A vasculitis (Henoch-Schönlein purpura). In most cases, the diagnosis is made on a clinical basis without a skin biopsy. METHODS: A systematic review of the literature was performed to examine the reported prevalence of vascular immune deposits in skin biopsies of patients with acute hemorrhagic edema of young children. RESULTS: Testing for vascular immune deposits was performed in 75 cases (64 boys and 11 girls aged from 3.5 to 72, median 11 months) published between 1970 and 2018. Vessel wall deposition of complement C3 was seen in 40 cases. Immunoglobulin M (N = 24), immunoglobulin A (N = 21), immunoglobulin G (N = 13), and immunoglobulin E (N = 3) were less frequently detected. Gender, age, clinical features, and disease duration were not statistically different in cases with and without vessel wall deposition of immunoglobulin A. CONCLUSION: Immune deposits in skin vessels, most frequently complement C3, are common in subjects with acute hemorrhagic edema of young children, providing furhter evidence that acute hemorrhagic edema, immunoglobulin A vasculitis, and pauci-immune vasculitides are different entities.

Classification criteria for autoinflammatory recurrent fevers.

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor-associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome.

OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

Towards a new set of classification criteria for PFAPA syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.