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Objectives To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. Methods This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. Results Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. Conclusion Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Objectives Previous studies suggest that exposure to inflammation in infancy may increase the risk for attention-deficit and hyperactivity disorder (ADHD). We studied the ADHD manifestations among 124 familial Mediterranean fever (FMF) patients and examined the relationship between FMF patient characteristics and ADHD. Methods Clinical, demographic, and genetic data were abstracted from patients’ medical records and supplemented by information obtained during clinic visits. ADHD manifestations were assessed using the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) questionnaire. Results ADHD was diagnosed in 42 (32.8%) FMF patients, a rate significantly higher than in unselected populations (∼8%). A majority (n = 27, 64.3%) had combined inattentive, hyperactive-impulsive manifestations. Eight (19%) had predominantly hyperactive-impulsive, and seven (16.6%) had predominantly inattentive symptoms. FMF patients with severe manifestations reported more ADHD symptoms. FMF patients with ADHD symptoms were less adherent to their treatment regimen, with only 61.9% of the patients with ADHD symptoms adhering to colchicine therapy compared to 92.7% of the patients without ADHD symptoms. Conclusion The high prevalence of ADHD characteristics in children with FMF may support the neuroimmune hypothesis that chronic inflammation increases the risk for ADHD. Children with FMF should be screened for ADHD as its presence may adversely affect adherence to treatment.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

The autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin(IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoringin vivodecay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-κB dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.

The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants in the AGTPBP1 gene. We conclude that complete loss-of-function of AGTPBP1 in humans, just like in mice and sheep, is associated with cerebellar and motor neuron disease, reminiscent of Pontocerebellar Hypoplasia Type 1 (PCH1).

We report manual external chest compression (MECC) as an effective treatment for acute respiratory failure due to severe air trapping. In this retrospective study, we describe our experience with MECC administered to five children suffering from severe air trapping as a consequence of severe asthma or bronchiolitis. These children were admitted to the Pediatric Intensive Care Unit (PICU) with clinical and blood gases parameters compatible with acute respiratory failure. Before intubation MECC was performed. The results of blood gasses before, during, and after MECC showed gradual changes in PCO2 over time indicating the improvement in tidal volume and ventilation. Respiratory failure resolved in all five children within 4 h with no complications. The need for intubation and mechanical ventilation was avoided, and all children were discharged from the PICU within 48 h.

Familial Mediterranean fever is a common autoinflammatory disease characterized by periodic attacks of fever and serositis. There are few reports describing neurological symptoms in patients with FMF. The aim of this study was to systematically assess the neurologic and developmental involvement in pediatric patients with FMF. Between the years 2016 and 2019, parents of children with FMF were asked to complete a questionnaire regarding the presence of neurological and developmental symptoms in their children with and without FMF. Demographic data, clinical characteristics, and disease course of FMF patients were collected from the medical charts. Neurodevelopmental manifestations were compared between the children with FMF and their siblings. A total of 205 children were enrolled (11.6 ± 4.7 years of age): 111 children with FMF and 94 healthy siblings in the control group. Neurological morbidity was frequently reported in children with FMF: 44 (40%) had recurrent headaches, 31 (28%) ADHD symptoms, 27 (24%) learning disabilities, and 10 (9%) febrile convulsions. Headaches and febrile convulsions were significantly more prevalent in children with FMF as compared to their siblings (ps < 0.05). ADHD and learning disabilities were associated with poor adherence to colchicine treatment.Conslusions: The present study found an increased prevalence of ADHD, learning disabilities, headaches, and febrile seizures in children with FMF. The findings underscore the importance of addressing the neurodevelopmental domain in children with FMF. In addition, detection and treatment of ADHD and learning disabilities could improve adherence with therapy and control of the underlying disease. What is Known: • Familial Mediterranean fever (FMF) is the most common inherited auto-inflammatory disease, characterized by recurrent attacks of fever, serositis, and arthritis. • Some previous case reports also described rare neurological manifestations in children with FMF. What is New: • The study found an increased prevalence of headaches, febrile seizures, ADHD, and learning disabilities, in children with FMF. • The findings underscore the importance of addressing the neurological domain in this population, which could potentially improve adherence with therapy and control of the underlying disease.

Background Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD). Objective To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family. Methods Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts’ colonies. Results Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098C>T (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found. Conclusions A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.

Objective To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)–associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection. Methods International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA–associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present. Results The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections. Conclusion The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD).To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family.Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts' colonies.Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098CT (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found.A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.

Regulatory T cells and T helper 17 cells are two recently described lymphocyte subsets with opposing actions. In this review, we discuss the mechanisms that promote development of these cells from common precursors and the specific factors that impact their cell numbers and function. Altered regulation of this key developmental checkpoint may contribute to the pathophysiology of autoimmune diseases by tipping the balance toward inflammation. We also present recent findings that suggest how the equilibrium between regulatory T cells and proinflammatory T helper subsets might be pharmacologically restored for therapeutic benefit.

Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient's PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient's NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient's NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.

Central nervous system (CNS) involvement, one of the most severe manifestations of Behçet's disease (BD), is uncommon in children. Because it is rare, the clinical features of this disease in children are not well characterised. Here we describe a teenager with BD which was disclosed following an episode of cerebral sinus vein thrombosis (CSVT) and review the available literature on children with CSVT associated with BD.A 12-year-old boy who presented with CSVT is described and the relevant literature, based on a Medline search from 1966 to January 2015 is reviewed.Twenty-three well-documented reports of children with CSVT and BD are described. This manifestation affected mainly males (61%) with a mean age of 12 years (range 4-18). BD was first diagnosed simultaneously or following CSVT in the majority of cases (75%). Multiple sinuses were involved in 30% of the cases. Thrombosis of additional large vessel was identified in 5 of the 23 children. The most common presenting symptom and signs were headache (91%), lasting more than 3 days in most cases (75%), followed by papilledema (43%), seizures (17%), and personality changes (9%). A mixed pattern of CNS involvement including both parenchymal involvement and CSVT, was demonstrated in only two patients (9%). Management of CSVT differed between reports.CSVT in children is a rarely reported manifestation of BD and has a characteristic clinical picture of a teenage boy presenting with prolonged headache, with no previous diagnosis of BD. A therapeutic approach has not been established yet.

In recent years, it has become increasingly clear that the term Juvenile Idiopathic Arthritis (JIA) comprises not one disease but several. Moreover, recent studies strongly suggest that some of these clinico-pathophysiologic entities appear to cross current diagnostic categories. The ultimate goal of the JIA classification is to facilitate development of better, more specific therapy for different forms of disease though improved understanding of pathophysiology. The past two decades have witnessed significant advances in treatment and improved outcomes for many children with chronic arthritis. However, understanding of the basic biologic processes underlying these diseases remains far from complete. As a result, even the best biologic agents of today represent "halfway technologies". Because they do not treat fundamental biologic processes, they are inherently expensive, need to be given for a long time in order to ameliorate the adverse effects of chronic inflammation, and do not cure the disease. Pediatric rheumatology is now entering an era in which diagnostic categories may need to change to keep up with discovery. A more precise, biologically based classification is likely to contribute to development of more specific and improved treatments for the various forms of childhood arthritis. In this review, we discuss how genetic, gene expression, and immunologic findings have begun to influence how these diseases are understood and classified.

Drug hypersensitivity syndrome (DHS) is a potentially life-threatening form of drug reaction that is particularly associated with anticonvulsants. The role of glucocorticoids (GC) for treatment of ...

In this article we describe three infants who suffered from a disorder characterized by splenomegaly, anemia, and severe infections beginning during the first months of life. Immunologic studies revealed agammaglobulinemia. However, normal numbers of lymphocytes and lymphocyte subsets were present in peripheral blood, and lymphocyte proliferation in responses to mitogenic stimulation in vitro was normal. Histologic and immunohistologic studies performed in one of the patients revealed lack of secondary follicles and follicular dendritic cells in lymphoid tissues and absence of plasma cells in the intestinal lamina propria. Similar findings have been observed in the hyper-IgM syndrome. However, these patients can be distinguished from currently recognized genetic variants of hyper-IgM syndrome on the basis of their clinical and histologic features, together with information obtained from DNA sequence analysis. Thus, their condition is likely to represent a novel form of primary immune deficiency with features of hyper-IgM syndrome.

Background: Sudden infant death syndrome (SIDS) is a diagnosis of exclusion that may be assigned only after investigations including a forensic autopsy are performed to exclude possible organic and environmental causes of death. Israeli society is influenced by the Jewish and Islamic faiths, which permit autopsy only under selected circumstances. Against this background, we carried out a study to determine what examinations are performed to investigate unexplained infant deaths in Jerusalem, Israel. Methods: We examined hospital, Ministry of Health and Ministry of Interior records of unexplained infant deaths in the Jerusalem district from the years 1996–2003. Results: Ninety six cases were identified from all sources. Forty nine (51%) infants were brought to a hospital at or near the time of death. Studies to determine the cause of death were performed in 54% of cases for which medical records were available for review. These studies included bacterial cultures (44%), skeletal surveys (12%), computerised tomography (3%) and metabolic studies (3%). Only one forensic autopsy was performed, and in no instance was the death site examined by medical personnel. There was a high rate of retrospective review by district health physicians. The most frequently assigned cause of death was SIDS. Conclusions: : The capacity of public health officials and forensic pathologists to investigate unexplained infant deaths is strongly affected by the legal, religious and political milieu in which they work. Efforts should be made to develop socially acceptable methods of improving the quality of infant death investigations in Jerusalem.

Uteroglobin (UG) is a pleiotropic protein with anti-inflammatory properties. Mice rendered genetically incapable of expressing UG develop a form of renal disease that closely resembles human IgA nephropathy (IgAN). Furthermore, a single nucleotide polymorphism in the UG gene (A38G) has been associated with rapid progression of human IgAN. We examined whether the A38G polymorphism is associated with childhood Henoch-Schonlein purpura (HSP), a form of vasculitis associated with IgAN-like renal disease. We examined the prevalence of the A38G polymorphism in 34 children with HSP and in 38 ethnically matched controls. Only one patient had clinically evident renal involvement. As compared with controls, the prevalence of the 38G allele was slightly increased in children with HSP, but this increase was not statistically significant. Our results do not support a role for UG in susceptibility to childhood HSP in the population studied. Larger studies involving more patients with renal disease will be necessary to define whether UG is associated with increased risk for HSP nephritis.

To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection.International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present.The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections.The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, mainly affecting ethnic groups living at Mediterranean basin. FMF is characterized by recurrent, self-limited episodes of fever and serositis. The diagnosis is difficult in the presence of atypical signs, which may result in significant delay in initiating treatment. As autoinflammatory diseases may have overlapping symptoms, strict diagnostic criteria are essential. Since the discovery that mutations in the gene MEFV underlie FMF, molecular genetic testing has been used as a diagnostic adjunct, especially in atypical cases. However, despite progress in the understanding of FMF disease mechanisms during the past 15 years; the diagnosis is still based on clinical criteria. Several sets of diagnostic criteria have been proposed and used. Existing diagnostic criteria should be modified to include genetic data, and need to be more widely validated.

The year 2012-2013 has been a fertile one in the area of FMF inquiry. Recent studies have led to further insight into the possible mechanisms whereby pyrin mutations might cause the auto-inflammatory phenotype that is characteristic of FMF. Evidence-based guidelines for diagnosis of FMF, including the role of genetic testing, have become available. Risks for colchicine resistance have been partially defined, and a randomised, controlled trial showing efficacy of an interleukin-1 antagonist for treatment of colchicine-resistant or intolerant FMF patients was reported. In this review, we summarise these and other salient findings from the recent FMF literature, and discuss their significance for the clinician.

Background Veno-occlusive disease with immunodeficiency (VODI) is an autosomal recessive disorder of combined immunodeficiency (CID) and hepatic injury. Hematopoietic stem cell transplantation (HSCT) - the only definitive treatment for CID - appeared to have a high rate of complications in a previous report. In this study, we describe a new group of patients with VODI highlighting further clinical and immunologic aspects of this disease and re-evaluating the effectiveness of HSCT for the treatment of this disorder. Patients and methods Review of clinical data, immunologic features, molecular studies, treatment, and final outcome of eight kindred members with VODI. Results The patients described had clinical and immunologic findings consistent with VODI. The molecular studies revealed a new mutation in the SP110 gene. HSCT was carried out in five patients and was successful in three. Conclusions The diagnosis of VODI should be considered in all patients regardless of ethnicity with a severe combined immunodeficiency (SCID)-like presentation, especially with a normal mitogen response, or with signs of hepatic injury. VODI is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of disease using appropriate conditioning.

Objectives Systemic lupus erythematosus (SLE) occurs more commonly in females than in males. Recent evidence suggests that genetic factors transmitted by the X-chromosome may confer increased risk for autoimmune disease in general, and for SLE in particular. It is therefore possible that X-chromosome polysomy might confer further increased risk for lupus. In addition to describing the clinical and immunologic features of a young woman with polysomy-X and SLE, we sought to review all other published cases associating female or male polysomy-X with SLE or other forms of autoimmunity. Methods We report a case of a prepubertal girl with polysomy-X and SLE. We performed a systemic literature review for cases of polysomy-X and SLE and summarize previously published cases. In addition, we reviewed reports concerning the possible association between SLE and other connective tissue diseases and male polysomy-X. Results An 11-year-old girl with tetrasomy-X (48 XXXX karyotype) presented with prolonged fever. Workup led to the diagnosis of SLE, and subsequent renal biopsy revealed mild diffuse mesangial proliferative glomerulonephritis. Two additional cases of SLE in women with 47 XXX and one of 48 XXXX karyotype were found in a literature review and compared to the present case. We identified studies that found X-chromosome polysomy to be over-represented in male patients with SLE and case descriptions of connective tissue diseases occurring in patients with polysomy-X. Conclusion No consistent pattern of disease was observed in female polysomy patients with SLE. Taken together with the data concerning the frequency of polysomy-X among males with SLE, our findings provide additional support for the hypothesis that X-chromosome polysomy may confer increased susceptibility to SLE. Molecular mechanisms that might account for this phenomenon are discussed.

Aim: To describe a possible relationship between Henoch-Schonlein purpura and rheumatic fever. Methods: Patients with features of both diseases were identified by reviewing the hospital records. Medline and reference lists from published articles were used to search for previous reports of the two conditions occurring simultaneously. Results: Three newly described cases, and three previous reports of Henoch-Schonlein purpura associated with rheumatic carditis or chorea were identified. Conclusions: The coexistence of these two disorders in some patients supports the view that Group A streptococcus may have a pathogenic role in Henoch-Schonlein purpura.

Common variable immunodeficiency (CVI) is a condition characterized by hypogammaglobulinemia and impaired antibody responses, resulting in recurrent bacterial infections in untreated patients. In addition, affected individuals exhibit an increased incidence of autoimmunity, malignancy, and certain viral infections, suggesting the presence of an underlying generalized immune dysregulation. We have previously described a subgroup of CVI patients in whom T cells within PBMC populations exhibit a selective defect in lymphokine production. IL-2, IL-4, and IL-5 mRNA production was impaired in these patients, while proliferation, IL-2R expression, and c-myc mRNA production were normal. In the present series of experiments, using highly purified CD4+ T cells prepared by negative selection, we show that this lymphokine production defect is a primary abnormality of CVI CD4+ T cells: whereas CD4+ T cells from CVI patients proliferate normally in response to stimulation by PHA, staphylococcal enterotoxin B (SEB), or anti-CD2 antibodies, these stimuli induce significantly less IL-2 production than observed with CD4+ T cells from normal individuals. Furthermore, we show that this IL-2 production defect is not due to an accessory cell abnormality, since it was seen in the presence of normal (allogeneic) accessory cells, and patient accessory cells supported normal amounts of IL-2 production by PHA-stimulated CD4+ T cells obtained from normal individuals. Of interest, we also found that while IL-2 production by CD4+ T cells from CVI patients induced by stimulation with immobilized anti-CD3 antibody was reduced compared to CD4+ T cells from normal control individuals, this reduction was not statistically significant. Furthermore, stimulation of both CVI patient and normal CD4+ T cells with either ionomycin + phorbol myristate acetate or a combination of immobilized anti-CD3 antibody plus anti-CD28 antibody resulted in a 50-fold increase in IL-2 production compared to stimulation with immobilized anti-CD3 antibody alone, and, under these conditions, CVI and normal CD4+ T cells produced equivalent amounts of IL-2. Finally, minor defects in interferon-γ production by CD4+ T cells from CVI donors were observed, but these were less severe than the IL-2 production defects and were not statistically significant. We conclude that a primary abnormality of lymphokine production exists in the CD4+ T cells of a subset of patients with CVI. The fact that the IL-2 production defect is more severe upon stimulation with superantigen as opposed to anti-CD3 antibody, and could be overcome by stimulation with ionomycin + phorbol myristate acetate or by costimulation with immobilized anti-CD3+ anti-CD28 antibodies, implies that this defect is due to impairment of a specific signaling pathway.

Human cytomegalovirus (HCMV) is familiar to pediatric rheumatologists mainly as a cause of opportunistic disease in pharmacologically immune suppressed patients. However, HCMV also has a variety of immuno-modulatory effects, through which it may influence the course of rheumatic conditions. In this article we discuss the interplay between HCMV and the immune system, and review the clinical manifestations, diagnosis, and treatment of HCMV infection in children with rheumatic disease.

Attention deficit hyperactivity disorder (ADHD) is a developmental neuropsychiatric disorder characterized by inappropriate levels of inattention, impulsivity and hyperactivity. The cause of ADHD is unknown, but may involve both genetic and environmental factors. It has been suggested that exposure to inflammation in infancy may increase the risk for ADHD in later life. Familial Mediterranean Fever (FMF) is the most common inherited autoinflammatory disorder. In many FMF patients the inflammation persists in attack-free periods. The prevalence of ADHD among FMF patients has not been studied previously.

Chronic granulomatous disease is a rare disorder in which the phagocytes fail to produce hydrogen peroxide. The patients are predisposed to bacterial and fungal infections. Prophylactic antibiotics and interferon gamma have reduced bacterial infections, but there is also the danger of life-threatening fungal infections. We assessed the efficacy of itraconazole as prophylaxis against serious fungal infections in chronic granulomatous disease.Thirty-nine patients at least 5 years old (6 female and 33 male; mean age, 14.9 years) were enrolled in a randomized, double-blind, placebo-controlled study. After the initially assigned treatment, each patient alternated between itraconazole and placebo annually. Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day. The primary end point was severe fungal infection, as determined by histologic results or culture.One patient (who had not been compliant with the treatment) had a serious fungal infection while receiving itraconazole, as compared with seven who had a serious fungal infection while receiving placebo (P=0.10). No patient receiving itraconazole but five patients receiving placebo had a superficial fungal infection. No serious toxic effects were noted, although one patient had a rash and another had elevated results on liver-function tests; both of these effects resolved with the discontinuation of itraconazole.Itraconazole prophylaxis appears to be an effective and well-tolerated treatment that reduces the frequency of fungal infections in chronic granulomatous disease, but monitoring for long-term toxic effects is warranted.

To the Editor: Chronic recurrent multifocal osteomyelitis (CRMO) is a form of chronic nonbacterial osteitis (CNO) characterized by one or more lytic bone lesions with no identifiable cause1. The metaphyses of long bones and the clavicle are most frequently affected, although any bone may be involved. Most cases begin in childhood, and follow an intermittent course. Pain is the most common presenting symptom. Affected individuals are sometimes febrile, and acute-phase reactants may be increased, pointing to the inflammatory expression of this condition. Lesions may resolve at or before the time of puberty, but in some cases skeletal deformity and/or disability may occur2. We describe 2 children with CRMO whose symptoms persisted after trials of nonsteroidal antiinflammatory medication, glucocorticoids, and methotrexate (MTX). Combination therapy with MTX and etanercept resulted in amelioration of pain, accompanied in one patient by radiographic improvement in a lytic bone lesion. A 4-year-old boy developed pain in his right foot and refused to walk for 2 months. Plain radiographs showed normal-appearing vertebra. A bone scan disclosed increased uptake in the right talus and navicular bone. He received several courses of intravenous and oral antimicrobials, without improvement. Fever was absent, C-reactive protein was normal, and erythrocyte sedimentation rate (ESR) was mildly increased to 23 mm/h. A second bone scan performed 2 months later showed increased radionuclide uptake in the L4 and L5 vertebra. Focal magnetic resonance imaging (MRI) revealed vertebral abnormalities consistent with CRMO including increased signal intensity of the vertebral marrow (Figure 1A). Talar biopsy was nonrevealing, showing bone fragments with myxoid-appearing fibrous stroma. Naproxen 10 mg/kg/day was given, without improvement. Prednisone 2 mg/kg/day was added for 3 weeks, … [↵][1]Address correspondence to Dr. Eisenstein; E-mail: emeisenstein{at}gmail.com [1]: #xref-corresp-1-1

A multinational collaborative effort aimed to develop a new set of criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sjia) is ongoing. The data-collection phase of the project has been recently completed

CD2 is a glycoprotein expressed on the surface of human T cells that mediates adhesion between T cells and antigen presenting cells. CD2 also functions in concert with the T cell receptor to transduce signals that lead to T cell activation. The CD8 and CD4 molecules are transmembrane glycoproteins that are expressed on mutually exclusive populations of mature T cells and bind to determinants on major histocompatibility complex class I and class II molecules respectively. Like CD2, CD4 and CD8 function to promote adhesion between T cells and antigen presenting cells and potentiate signaling via the T cell receptor. We studied a patient with idiopathic lymphopenia and disseminated infection with Mycobacterium avium. The patient also suffered from recurrent deep venous thrombosis in association with anticardiolipin and anti-DNA antibodies. Peripheral blood T cells from this patient were polyclonal and expressed no detectable CD2 RNA or protein as determined by northern blotting, immunofluorescent staining with anti-CD2 antibodies, and failure to form rosettes with sheep red blood cells. In addition, the majority (85%) of this patient's T cells did not express either CD4 or CD8 but did express the alpha/beta T cell receptor. T cells from this patient failed to respond to stimulation with alloantigen or specific antigen. In contrast, there was a normal response to stimulation with immobilized anti-CD3 antibody. The clinical and immunologic findings in this patient provide in vivo evidence that the accessory molecules CD2, CD4, and CD8 play important roles in the regulation of normal human T cell activation.

Studies conducted in vitro and in animals suggest that cytokine signals to monocytes or macrophages by interferon gamma are important in the containment and clearance of disseminated nontuberculous mycobacterial infections.We studied seven patients with refractory, disseminated nontuberculous mycobacterial infections who were not infected with the human immunodeficiency virus. Three patients were from a family predisposed to the development of Mycobacterium avium complex infections; four patients had idiopathic CD4+ T-lymphocytopenia. Their infections were culture- or biopsy-proved, involved at least two organ systems, and had been treated with the maximal tolerated medical therapy. Cellular proliferation, cytokine production, and phagocyte function were assessed in peripheral-blood cells. Interferon gamma was administered subcutaneously two or three times weekly in a dose of 25 to 50 micrograms per square meter of body-surface area in addition to antimycobacterial medications. Clinical effects were monitored by cultures, biopsies, radiographs, and in one patient a change in the need for paracentesis.In response to phytohemagglutinin, the production of interferon gamma by mononuclear cells from the patients was lower than in normal subjects (P0.001), whereas stimulation with ionomycin and phorbol myristate acetate led to normal production of interferon gamma in the patients. Within eight weeks of the start of interferon gamma therapy, all seven patients had marked clinical improvement, with abatement of fever, clearing of many lesions and quiescence of others, radiographic improvement, and a reduction in the need for paracentesis.Interferon gamma in combination with conventional therapy may be effective for some cases of refractory disseminated nontuberculous mycobacterial infection.

This unit describes procedures for the isolation of pure human B cell populations. Two broad approaches to the isolation of pure human B cell populations are available, one based on techniques of negative selection and the other using positive selection. The negative selection approach has the advantage that the purified B cells obtained are less likely to be functionally altered by the isolation procedure. In addition, this approach does not require the use of expensive antibodies, which are usually the key element of a positive selection procedure. On the other hand, negative selection has the disadvantage that cell types not specifically targeted for removal (such as eosinophils) may be present in the final cell population. The positive selection method is an immunomagnetic positive selection using magnetic beads conjugated directly to an antibody specific for the B cell membrane determinant CD19. Also presented is a Support Protocol detailing the preparation of neuraminidase-treated sheep red blood cells for use in rosetting.

Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In ...

Common variable immunodeficiency (CVI) is a heterogeneous condition marked by a number of different immunologic defects. One group of patients, perhaps 60% of the CVI group as a whole, is characterized by T cells that produce reduced amounts of IL-2 (mRNA and protein product), IL-4, and IL-5 (mRNA) when stimulated with phytohemagglutinin. This defect does not extend to all lymphokines, however, because the cells produce normal amounts of interferon-gamma (mRNA and protein product) when exogenous IL-2 is present. Recently, we have reexamined the T cell lymphokine production defect using a panoply of T-cell activation stimuli and have shown that the defect is a subtle one that depends on activation of the cell via the CD3-T-cell receptor complex. Because T cells proliferate normally when stimulated via this receptor, this finding suggests the presence of a "downstream" defect, perhaps one involving the factors that are necessary for activation of lymphokine genes. A second form of CVI, in this case involving approximately 30% of the CVI group as a whole, is characterized by a reduced CD4/CD8 ratio and elevated numbers of CD8+ T cells bearing the CD57 marker. Although the CD4+ T cells in this patient group elaborate normal amounts of IL-2 under various activation conditions, their CD8+ T cells produce increased amounts of interferon-gamma. Furthermore, the CD8+ T cells in this case act as "suppressor" T cells, which suppress IgG production but not IgM production of purified (normal) SAC+, IL-2-induced B cells.(ABSTRACT TRUNCATED AT 250 WORDS)