Thrombotic manifestations in pediatric Behcet syndrome: A multicenter comparative study from the EUROFEVER registry.

INTRODUCTION: Vascular events account for a considerable burden of morbidity and mortality in Behçet syndrome (BS). Thrombosis occurs in 1.8-21 % pediatric BS patients, even if the real prevalence is still largely unknown. OBJECTIVES: To report clinical features and outcomes of pediatric BS patients with thrombosis and to compare the demographic and clinical characteristics of BS patients with and without thrombosis. METHODS: Retrospective data collection of BS patients with thrombosis (T+) included in the EUROFEVER registry. BS patients without thrombosis (T-), belonging to the same rheumatology units, were matched in a 2:1 ratio. RESULTS: 37 T+ were compared to 74 T- patients. At onset, ICBD criteria fulfillment was higher in the T- group (p = 0.015). Caucasian patients were more often T-, Turkish patients were more frequent in T+ group (p = 0.002). At onset, pustulosis was most frequently observed in the T- (p < 0.001) as well as gastrointestinal symptoms (p < 0.001) and ocular involvement (p = 0.022). Neurological symptoms were more often described in T+ (p = 0.034). As for T+, thrombosis was reported at BS presentation in 8/37 (21.6 %). For the T + e patients who developed thrombosis later, oral aphthosis (p = 0.003), genital aphthosis (p = 0.014) were more frequently observed at BS onset, while pustulosis (p = 0.005) and fever (p = 0.043) coexisted with thrombosis. Thrombosis was mainly venous (26/37,70.3 %), involving the cerebral sinuses (21/37, 56.8 %). After thrombosis, 35/37 (94.6 %) T+ patients received an immunomodulatory treatment compared with 16/29 (55.2 %) pre-thrombosis. A recurrence was reported in 6/31(19.4 %). CONCLUSION: Thrombosis was reported at BS presentation in one fifth of cases. Pustolosis and fever were more frequently concomitant to thrombosis. Sinus veins were the most frequent site.

Viral infection in chronic otitis media with effusion in children.

Background: The role of respiratory viruses in chronic otitis media with effusion (COME) in children is not clearly defined. In our study we aimed to investigate the detection of respiratory viruses in middle ear effusions (MEE) as well as the association with local bacteria, respiratory viruses in the nasopharynx and cellular immune response of children with COME. Methods: This 2017-2019 cross-sectional study included 69 children aged 2-6 undergoing myringotomy for COME. MEE and nasopharyngeal swabs were analyzed via PCR and CT-values for the genome and loads of typical respiratory viruses. Immune cell populations and exhaustion markers in MEE related to respiratory virus detection were studied via FACS. Clinical data including the BMI was correlated. Results: Respiratory viruses were detected in MEE of 44 children (64%). Rhinovirus (43%), Parainfluenzavirus (26%) and Bocavirus (10%) were detected most frequently. Average Ct values were 33.6 and 33.5 in MEE and nasopharynx, respectively. Higher detection rates correlated with elevated BMI. Monocytes were elevated in MEE (9.5 ± 7.3%/blood leucocytes). Exhaustion markers were elevated on CD4+ and CD8+ T cells and monocytes in MEE. Conclusion: Respiratory viruses are associated with pediatric COME. Elevated BMI was associated with increased rates of virus associated COME. Changes in cell proportions of innate immunity and expression of exhaustion markers may be related to chronic viral infection.

Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative.

BACKGROUND: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies. METHODS: The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice. RESULTS: The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS. CONCLUSIONS: The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.

Kawasaki disease in children and adolescents: clinical data of Kawasaki patients in a western region (Tyrol) of Austria from 2003-2012.

BACKGROUND: Kawasaki disease (KD) is a rare vasculitis seen predominantly in children. In developing countries, it is the leading cause of childhood-acquired heart disease. Besides a case report from 1981 there have been no data published dealing with the epidemiology and clinical aspects of KD in Austria. METHODS: The purpose of the present study was to investigate the clinical spectrum of KD in a geographically determined cohort of infants, children, and adolescents that were diagnosed and treated at the University Hospital of Innsbruck from 2003-2012. RESULTS: Thirty-two patients were included in the study with a median age of 32.96 months (2-192). 59.4% of the patients were aged between six months and four years. The male-to-female ratio was 1:1.13. Clinical examination revealed non-purulent conjunctivitis and exanthema as the most common symptoms (84.4%). 75% showed oropharyngeal changes, 21.9% had gastrointestinal complaints such as diarrhoe, stomachache or vomiting prior to diagnosis. One third of the patients were admitted with a preliminary diagnosis, whereas 78.1% were pre-treated with antibiotics. The median fever duration at the time of presentation was estimated with 4.96 days (1-14), at time of diagnosis 6.76 days (3-15).75% were diagnosed with complete KD, and 25% with an incomplete form of the disease. There was no significant difference in the duration of fever neither between complete and incomplete KD, nor between the different age groups. Typical laboratory findings included increased C-reactive protein (CRP) (80.6%) and erythrocyte sedimentation rate (ESR) (96%),leukocytosis (48.4%) and thrombocytosis (40.6%) without any significant quantitative difference between complete and incomplete KD. Coronary complications could be observed in six patients: one with a coronary aneurysm and five with tubular dilatation of the coronary arteries. Our patient cohort represents the age distribution as described in literature and emphasizes that KD could affect persons of any age. The frequency of occurrence of the clinical symptoms differs from previous reports - in our study, we predominantly observed non-purulent conjunctivitis and exanthema. CONCLUSION: KD should always be considered as a differential diagnosis in a child with fever of unknown origin, as treatment can significantly decrease the frequency of coronary complications.

Neuropsychological profile of children after an episode of neuroborreliosis.

BACKGROUND: In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched. OBJECTIVES: The study aimed to investigate cognitive functions and behavioral problems in children after LNB. PATIENTS AND METHODS: A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/µL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered. RESULTS: Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints. CONCLUSION: Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome.

Increased replication of CD4+ naive T cells and changes in T cell homeostasis in a case of acute exacerbation of juvenile idiopathic arthritis: a case comparison study.

INTRODUCTION: Juvenile idiopathic arthritis is a heterogeneous T cell-mediated autoimmune disease with symptoms of premature aging of the immune system (immunosenescence). The present work is an investigation of immunosenescence parameters, such as quantity of naive and CD28- T cells, T cell receptor excision circles, relative telomere length and alterations of peripheral T cell replication, and was performed via comparison of a case of acute exacerbation of juvenile idiopathic arthritis against six patients with juvenile idiopathic arthritis with disease remission and six age-matched healthy donors over a follow-up course of 12 months. CASE PRESENTATION: Phenotypical T cell characterization and intracellular interferon γ, tumor necrosis factor α, and interleukin 2 production were studied in peripheral blood mononuclear cells from seven patients with juvenile idiopathic arthritis and six healthy control donors, with findings determined by flow cytometry. T cell receptor excision circles and relative telomere length quantification were performed on deoxyribonucleic acid isolated from naive (CD4+CD28+CD45RA+) T cells and investigated via reverse transcription polymerase chain reaction. Ki67 expression was studied by immunohistochemistry on naive T cells. The non-parametric Mann-Whitney U test and Wilcoxon test for two independent groups of variables were used to compare healthy donors with patients with juvenile idiopathic arthritis. During follow-up, patients with juvenile idiopathic arthritis showed lower total counts of naive and CD28-expressing T cells compared to healthy donors. Acute exacerbation led to low naive and CD28+ T cell populations and elevated proportions of Ki67-expressing CD4+ naive T cells. In conditions of exacerbation, T cell receptor excision circle numbers were in the lower range in patients with juvenile idiopathic arthritis and increased after follow-up. Healthy donors showed significantly higher relative telomere lengths compared to patients with juvenile idiopathic arthritis. CONCLUSIONS: This investigation illustrates that the changes in T cell homeostasis in patients with juvenile idiopathic arthritis may be the result of several mechanisms, such as diminished thymus function and peripheral exertions to maintain the peripheral T cell pool. The results also demonstrate that hallmarks of immunosenescence such as decreased naive T cell levels and lower T cell receptor excision circle numbers can only be interpreted together with replication markers such as relative telomere length or Ki67 expression.

Analysis of the classical, alternative, and mannose binding lectin pathway of the complement system in the pathogenesis of oligoarticular juvenile idiopathic arthritis.

The complement system plays a role in the pathogenesis of some autoimmunopathies. This longitudinal study evaluates the contribution of the complement system in the pathogenesis of oligoarticular juvenile idiopathic arthritis (JIA). Serum of the peripheral blood and the synovial fluid were investigated for the activity of the classical (CP), the mannose binding lectin (MBL), and the alternative pathway (AP). A total of 12 samples from peripheral blood (PB) and two samples from synovial fluid (SF) of girls with oligoarticular JIA were investigated in a longitudinal observation from the time point of the diagnosis of JIA. The differences between the complement activity in the PB and in the SF were extremely statistically significant (CP and MBL: P < 0.0001; AP: < 0.0087). The activity of the CP and the MBL pathway was reduced. The AP is the main contributor in the pathogenesis of oligoarticular JIA. Anti-C5 therapy may be an option to avoid the creation of the membrane attack complex.

Takayasu arteritis in children and adolescents.

Takayasu arteritis is a devastating vasculitis of the aorta and its major branches. The clinical manifestations in paediatric patients are less specific than in adults: in children the disease presents with fever, arthralgias and hypertension. Intramural inflammation results in narrowing of the blood vessel lumen and therefore hypoperfusion of the parenchyma. Conventional angiography is the gold standard diagnostic procedure. Corticosteroids, cyclophosphamide, MTX and biological therapies such as TNF-α blocking agents are treatment options.

The turnover of synovial T cells is higher than in T cells in the peripheral blood in persistent oligoarticular juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) summarizes a group of inflammatory diseases of childhood. The etiology remains still unclear. In JIA, T cells have been demonstrated to play key roles in the pathogenesis. T-cell proliferation in JIA may be different in the peripheral blood (PB) and the synovial fluid (SF). The aim of this study is to demonstrate the turnover of T cells in the PB and SF of patients with persistent oligoarticular JIA (oJIA) compared to controls. Matched pairs of samples were investigated derived from PB and SF of nine patients with persistent oJIA. The cells from PB and SF were determined by flow cytometry. The majority of the PBMC and IAMC were in phase G0/G1, with fewer than 1% in S phase. In the SF, the percentage of cells in the S phase are higher than in the PB. The percentage of cells in the S phase in SF are equal to the result in the control group. In conclusion, the turnover of synovial T cells in persistent oJIA is higher than in the PB.

Quantitative alterations of CD8+ T cells in juvenile idiopathic arthritis patients in remission.

The study was aimed to investigate whether quantities of CD8(+) T cell subsets are normal in juvenile idiopathic arthritis (JIA) patients with disease remission compared to age-matched healthy donors (HD) and whether chronological age may have an impact on proportions of naive CD8(+) T cells. CD8(+) T cell subsets were analyzed in 17 JIA patients and 32 age-matched HD by flow cytometry. JIA patients showed lower CD3(+)CD8(+) T cells compared to HD. Total counts of CD8(+)CD28(+) and CD8(+)CD28(+)CD45RA(+) T cells were inversely correlated to chronological age in JIA patients and HD. In JIA patients, percentages of CD8(+)CD28(+)CD45RA(+) T cells and of CD62L-expressing CD8(+)CD28(+)CD45RA(+) T cells showed a negative correlation with age. The trend to lower CD28(+)CD45RA(+) T cell proportions in aged JIA patients in remission may reflect a disturbed T cell homeostasis independently of disease activity and may be due to an intrinsic effect in reconstitution of the peripheral T cells.

Indications for a disturbed peripheral T-cell homeostasis in juvenile idiopathic arthritis (JIA): absent expansion of CD28 T-cells and no decrease of naive T-cells in cytomegalovirus-positive patients with JIA.

OBJECTIVE: To investigate the influence of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on CD28-expressing T-cell subpopulations and replicative senescence of naive T-cells as a marker for aging of the immune system in children with juvenile ideopathic arthritis (JIA). METHODS: T-cell subpopulations were analyzed from 24 patients with JIA and 61 healthy age-matched controls by fluorescence activated cell sorting. Relative telomere length (RTL) in CD4+CD28+CD45RA+ (naive) T-cells was measured by quantitative polymerase chain reaction. RESULTS: Although confirming known data of expansions of CD28- T-cells and tendency of decreasing naive T-cells in CMV-seropositive healthy individuals, our findings did not show a marked influence of latent EBV or CMV infection on CD28-expressing T-cells in patients with JIA. In contrast, CMV was an independent factor for loss of CD28, regardless of age, in healthy controls. Irrespective of serology results for CMV or EBV, patients with JIA showed signficantly decreased RTL compared to age-matched controls. Regression lines for RTL and age revealed decreased RTL with advancing age in CMV-positive and EBV-positive subjects. The evidence that findings for CMV-positive JIA patients did not resemble the findings of healthy CMV-positive controls, namely expansion of CD28- T-cells and decrease of naive T-cells, may support the theory of a disturbed peripheral T-cell homeostasis in JIA. CONCLUSION: Diminished mechanisms of T-cell homeostasis and premature aging of the immune system may play a role in the pathogenesis of JIA.