[show abstract][hide abstract] ABSTRACT: Kawasaki disease (KD) is an acute paediatric vasculitis. The psychosocial consequences of this sudden illness for parents are unknown. This study aimed to evaluate health related quality of life (HRQOL) and parental perceptions of child vulnerability (PPCV) in parents of children with KD, and to identify variables associated with PPCV.
This cross-sectional study included 288 parents (83% mothers) of KD patients (mean age 8.7 years). HRQOL was assessed using the TNO-AZL Questionnaire for Adult's HRQOL (TAAQOL) and PPCV using the Child Vulnerability Scale (CVS). Scores of KD parents were compared with reference groups of Dutch parents. Logistic regression analyses were performed to examine associated variables.
The HRQOL of KD parents was comparable to the HRQOL of parents of healthy children. However, KD parents showed significantly higher PPCV, regarding both the median CVS total score and the percentage in the clinical range. No differences were found in CVS outcomes between KD parents and parents of a chronically ill child. None of the studied parental, child and disease characteristics were significantly associated with PPCV.
Parents perceived their KD child more vulnerable to illness than healthy children, while in reality the majority had fully recovered from KD. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Human blood neutrophils normally express two FcγRs (FcγRIIa and FcγRIIIb) that, upon multivalent binding of IgG in immune complexes or on opsonized targets, mediate responses such as phagocytosis, Ab-dependent cellular cytotoxicity, and respiratory burst. Allelic variants have been described for both FcγRIIa (131H/R) and FcγRIIIb (NA1/NA2/SH), with different binding affinity for IgG subclasses. Because neither of these variants acts alone, we have set out to systematically analyze in a large cohort of healthy FCGR2/3-genotyped volunteers how the different haplotypes of neutrophil FcγRs functionally interact. Maximal IgG-induced H2O2 production by neutrophils from individuals with different (homozygous) haplotypes was observed in the following order: 131HH-NA2NA2 > 131RR-NA1NA1 > 131HH-NA1NA1 > 131RR-NA2NA2. Although FcγRIIa 131H is known to bind IgG1 and IgG2 more avidly, no such differences in affinity are known for FcγRIIIb variants. Nonetheless, a remarkable impact of the FcγRIIIb variants on IgG-mediated neutrophil activity was thus demonstrated, which was not explained by differences in FcγR surface expression. The FcγR expression profile was changed by overnight G-CSF/IFN-γ activation of the neutrophils and eliminated any haplotypic impact on the respiratory burst. To our knowledge, our results are the first to provide an integrated functional analysis of neutrophil FcγR haplotypes and suggest that particularly the early phase of IgG-mediated neutrophil reactivity is influenced by FCGR2/3 genotypic variation.
The Journal of Immunology 02/2014; · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Retrotransposon-mediated insertion of a LINE-1 or an Alu element into a human gene is a well known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X chromosome. In a Dutch male patient with chronic granulomatous disease a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense polyA tail, target site duplication and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate the incidence, disease presentation, treatment and cardiac outcome of Kawasaki disease (KD) in the Netherlands.
The national Dutch Pediatric Surveillance Unit (DPSU) was used to prospectively register new KD cases from 2008 through 2012. Questionnaires were sent to pediatricians to obtain clinical information.
Nationwide 341 cases were reported during the 5-year study period, of which 319 questionnaires (93.0%) were returned. The mean incidence of KD was estimated to be 5.8/100,000 children <5 years of age. The median age at disease onset was 2.4 years (range 0.1-14.6 years) and 79.2% of cases were <5 years of age). The male to female ratio was 1.5 to 1. Incomplete KD was diagnosed in 22.3% of cases and these cases were significantly younger than complete cases (median, 1.1 [0.1-13.7] versus 2.8 [0.2-14.6] years, p<0.001). In total, 308 patients (96.6%) received IVIG. Retreatment with IVIG was given in 71 (23.1%), and additional steroid treatment in 17 patients (5.5%). During the acute phase coronary artery aneurysms (CAA) developed in 43 cases (13.5%). Multivariate logistic regression analysis showed that male gender, delay of treatment (>10 days) and IVIG retreatment were independent risk factors for CAA development.
This prospective study of KD in the Netherlands revealed a mean annual incidence of 5.8/100,000 children <5 years of age. Clinicians should consider the diagnosis of KD in young (male) children with persistent inexplicable fever to start IVIG treatment within 10 days to prevent development of CAA.
The Pediatric Infectious Disease Journal 01/2014; · 3.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: MBL-deficiency has been associated with an increased frequency and severity of infection, in particular in children and under immunocompromized conditions. In an open uncontrolled safety and pharmacokinetic MBL-substitution study using plasma-derived MBL (pdMBL) in MBL-deficient pediatric oncology patients, we found that despite MBL trough levels above 1.0μg/ml MBL functionality was not efficiently restored upon ex vivo testing. PdMBL showed C4-converting activity by itself, indicating the presence of MASPs. Upon incubation of pdMBL with MBL-deficient sera this C4-converting activity was significantly reduced. Depletion of the MASPs from pdMBL, paradoxically, restored the C4-converting activity. Subsequent depletion or inhibition of C1-inh, the major inhibitor of the lectin pathway, in the recipient serum restored the C4-converting activity as well. Complexes between MBL/MASPs and C1-inh (MMC-complexes) were detected after ex vivo substitution of MBL-deficient serum with pdMBL. These MMC-complexes could also be detected in the sera of the patients included in the MBL-substitution study shortly after pdMBL infusion. Altogether, we concluded that active MBL-MASP complexes in pdMBL directly interact with C1-inh in the recipient, leading to the formation of a multimolecular complex between C1-inh and MBL/MASPs, in contrast to the classical pathway where C1r and C1s are dissociated from C1q by C1-inh. Because of the presence of activated MASPs in the current pdMBL products efficient MBL-mediated host protection cannot be expected because of the neutralizing capacity by C1-inh.
[show abstract][hide abstract] ABSTRACT: To evaluate whether clinical disease activity findings during 1-year followup of patients with juvenile idiopathic arthritis (JIA) is associated with changes of magnetic resonance imaging (MRI)-based disease activity scores.
Patients with JIA who had active knee involvement were studied using an open-bore MRI. After followup of a median of 1.3 years, patients were re-evaluated and classified as improved or unimproved according to the American College of Rheumatology Pediatric-50 (ACR-Ped50) criteria. Baseline and followup MRI features were scored by 2 readers using the Juvenile Arthritis MRI Scoring (JAMRIS) system, comprising validated scores for synovial hypertrophy, bone marrow changes, cartilage lesions, and bone erosions.
Data of 40 patients were analyzed (62.5% female, mean age 12.2 yrs). After followup, 27 patients (67.5%) were classified as clinically improved, whereas 13 patients (32.5%) showed no clinical improvement. The clinically improved patients showed a significant reduction in synovial hypertrophy scores during followup (p < 0.001), with substantial effects (standardized response mean -0.70). No such changes were observed for any of the other MRI features. Significant differences were detected regarding a change in synovial hypertrophy scores comparing clinically improved and unimproved patients (p = 0.004), without statistically significant differences for changes in scores for bone marrow changes (p = 0.079), cartilage lesions (p = 0.165), and bone erosions (p = 0.078).
This is one of the first studies to provide evidence for MRI-based improvement upon followup in JIA patients with knee involvement. There is a strong association with clinical improvement according to the ACR-Ped50 criteria and changes in MRI-based synovial hypertrophy scores, supporting the role of MRI as a responsive outcome measure to evaluate disease activity with antiinflammatory treatment strategies.
The Journal of Rheumatology 12/2013; · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the value of magnetic resonance imaging (MRI) in discriminating between active and inactive juvenile idiopathic arthritis (JIA) patients and to compare physical examination outcomes with MRI outcomes in the assessment of disease status in JIA patients.
Consecutive JIA patients with knee involvement were prospectively studied using an open-bore MRI. Imaging findings from 146 JIA patients were analysed (59.6 % female; mean age, 12.9 years). Patients were classified as clinically active or inactive. MRI features were evaluated using the JAMRIS system, comprising validated scores for synovial hypertrophy, bone marrow oedema, cartilage lesions and bone erosions.
Inter-reader reliability was good for all MRI features (intra-class correlation coefficient [ICC] = 0.87-0.94). No differences were found between the two groups regarding MRI scores of bone marrow oedema, cartilage lesions or bone erosions. Synovial hypertrophy scores differed significantly between groups (P = 0.016). Nonetheless, synovial hypertrophy was also present in 14 JIA patients (35.9 %) with clinically inactive disease. Of JIA patients considered clinically active, 48.6 % showed no signs of MRI-based synovitis.
MRI can discriminate between clinically active and inactive JIA patients. However, physical examination is neither very sensitive nor specific in evaluating JIA disease activity compared with MRI. Subclinical synovitis was present in >35 % of presumed clinically inactive patients.
• MRI is sensitive for evaluating juvenile idiopathic arthritis (JIA) disease activity. • Contrast-enhanced MRI can distinguish clinically active and inactive JIA patients. • Subclinical synovitis is present in 35.9 % of presumed clinically inactive patients. • Physical examination is neither sensitive nor specific in evaluating JIA disease activity.
[show abstract][hide abstract] ABSTRACT: The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.
[show abstract][hide abstract] ABSTRACT: Mutations in the DOCK8 gene define the most common form of autosomal-recessive Hyper-IgE-syndrome (AR-HIES/OMIM#243700). In a patient with extensive molluscum contagiosum lesions, a homozygous DOCK8 gene deletion was demonstrated. In-vivo 18-FDG uptake showed multiple non-enlarged lymph nodes without uptake in the spleen. Lymph node biopsies for subsequent immunohistochemistry showed clear differences with the mouse model of DOCK8 deficiency in which these mice show no GCs. Unexpectedly, the patient's lymph nodes demonstrated lymphocyte polyclonality, follicular hyperplasia and an unusual IgE(+) plasma cell expansion. In contrast, the proliferative capacity of circulating B-cells was almost absent with little in-vitro Ig production or plasmablast formation. Also the T-cell proliferation indicated a partial defect. Hematopoietic stem cell transplantation (HSCT) was performed resulting in the disappearance of the molluscum contagiosum lesions. In sum, DOCK8 deficiency results in defective antibody responses and undirected plasma cell expansion in the lymph nodes, as part of a combined immunodeficiency cured by HSCT.
[show abstract][hide abstract] ABSTRACT: PURPOSE OF REVIEW: To show that skin symptoms help in the recognition of primary immunodeficiencies (PIDs). To analyze whether recent molecular data help in understanding genotype/phenotype relations. RECENT FINDINGS: Erythroderma in Omenn syndrome may be caused by either mutations in genes associated with severe combined immunodeficiency (SCID) in which the generation of some T cells is possible, which results in potentially autoreactive lymphoid clones, or by selective proliferation of revertant CD8 T cells in the skin due to clonal expansion in response to infections or autoantigens.The newborn eczematous eruption, which occurs mainly in the signal-transducer-and-activator-of-transcription-3 (STAT3) variant, helps to differentiate STAT3 from Dedicator of Cytokinesis 8-related Hyper-IgE-syndrome (HIES).Impaired T helper 17 cell (TH17) immunity [HIES and defects of autoimmune regulator element (AIRE), STAT-1, and interleukin17 receptor(IL17(R))] may give rise to localized chronic mucocutaneous candidiasis, whereas a defective innate immune system predisposes to systemic candidiasis [congenital neutropenia, neutrophil dysfunction, and caspase recruitment domain 9 (CARD9) deficiency].Noninfectious granulomas may be the presenting symptom in innate immunity defects [such as chronic granulomatous disease (CGD) or in predominantly humoral immunodeficiencies such as common variable immunodeficiency], as well as ataxia teleangiectasia or rare recombination-activating gene-deficient cases. SUMMARY: The skin is important in the diagnosis of PIDs. In particular eczematous lesions, erythroderma, noninfectious granuloma, and microbial manifestations may help to direct further diagnostic laboratory analysis.
Current opinion in pediatrics 06/2013; · 2.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is caused by genetic defects in cytotoxic granule components or their fusion machinery, leading to impaired Natural Killer (NK) cell and/or T lymphocyte (CTL) degranulation and/or cytotoxicity. This may accumulate into a life-threatening condition known as macrophage activation syndrome. STXBP2, also known as MUNC18-2, has recently been identified as the disease-causing gene in FHL5. A role for STXBP2 in neutrophils, and for neutrophils in FHL in general, has not been documented thus far. Here, we report that FHL5 neutrophils have a profound defect in granule mobilization, resulting in inadequate bacterial killing, in particular of Gram-negative Escherichia coli, but not of Staphylococcus aureus, which rather depends on intact NADPH oxidase activity. This impairment of bacterial killing may contribute to the apparent susceptibility to gastrointestinal inflammation in FHL5 patients.
[show abstract][hide abstract] ABSTRACT: Human natural killer (NK) cells are part of the ﬁrst line of defense
during innate immunity against viral infection or tumor development. They are also at the heart of many autoimmune diseases and
they can inﬂuence the outcome of organ transplantation. The cytotoxicity of NK cells is regulated through receptor molecules on
the surface, which keep the cells in a balanced state. This balance
is disturbed once a non-self or pathogenic factor is encountered.
An important group of molecules that regulates NK cell function
is the killer immunoglobulin-like receptor (KIR) family. This is a
family of highly homologous activating and inhibiting molecules
of which some components have been shown to bind human
leukocyte antigen class I (HLA-I) molecules. HLA molecules
play a critical role in a variety of diseases and their importance
in donor-recipient (mis)matching has proven to determine success
in most transplantation settings. The composition of KIR genes
and copy number variation in a large cohort of healthy Caucasian
controls was determined using a novel, accurate and validated
method for complete genotyping by multiplex ligation-dependent
probe ampliﬁcation. We have now studied the composition of
KIR and HLA-class I genes in cohorts of patients suffering from
spondyloarthropathy (HLA-B27+) and of patients with or without
cytomegalovirus (re)activation following kidney transplantation.
Knowledge of interactions between KIR and HLA help us to
better understand pathogenicity.