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Biomedical subjects

Ger T Rijkers

Publications and source records attributed to Ger T Rijkers.

At least 19 recordsLinked to original sources
PubMed2006

Anterior uveitis: a manifestation of graft-versus-host disease.

PURPOSE: To describe the occurrence of anterior uveitis along with systemic manifestations of chronic graft-versus-host disease (GVHD) after nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) in 3 patients with hematologic malignancies. DESIGN: Retrospective small case series. PARTICIPANTS: Three patients who underwent HSCT and 4 age- and gender-matched controls for cytokine analysis in ocular fluid. METHODS: Interventional study of patients who underwent HSCT. Screening for evidence of infectious causes and immunological analysis of ocular fluid samples. MAIN OUTCOME MEASURES: Clinical features of uveitis and results of aqueous analysis. RESULTS: Anterior uveitis developed during an exacerbation of chronic GVHD in 3 patients after allogeneic HSCT for hematologic malignancies. Patients exhibited no abnormalities on extensive uveitis screening, and in addition, serologic and wide-ranging aqueous analysis showed no evidence of recent infections. We observed signs of inflammation in the ocular fluid in 2 of 3 patients by the determination of different cytokines. No other explanation for uveitis was found except the exacerbation of GVHD. Treatment, both systemic and topical, directed to chronic GVHD induced remission of uveitis in all patients along with amelioration of other signs of GVHD. CONCLUSIONS: Anterior uveitis occurred in the wake of the acute exacerbation of chronic GVHD after HSCT and may represent an ocular manifestation of chronic GVHD.

Adult↗
PubMed2006

Impact of genetic variants in IL-4, IL-4 RA and IL-13 on the anti-pneumococcal antibody response.

BACKGROUND: Significant differences in immune responses upon vaccination have been described, suggesting genetics are important in determining the magnitude of vaccine responses. The interleukin (IL)-4 pathway, including IL-4, IL-13 and the IL-4 receptor alpha chain (IL-4 Ralpha), is central to humoral responses and therefore could have an impact on vaccine responsiveness. OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) in the IL-4, IL-13 and IL-4 RA genes influence pneumococcal serotype-specific IgG antibody responses. METHODS: SNPs in the IL-4 gene (C -589T, G2979T), the IL-13 gene (G -1112A, Arg130Gln) and in the IL-4 RA gene (Ile50Val, Gln551Arg) were investigated in isolation and in combination, for their influence on serotype-specific IgG antibody responses upon combined pneumococcal conjugate and polysaccharide vaccinations in children with a history of recurrent otitis media. RESULTS: Lower antibody responses were observed for alleles previously associated with atopy, IL-4 -589T, IL-4 2979T and IL-4 Ralpha 551Gln. Effects were stronger in gene haplotype combinations or in multiple haplotype combination analyses. CONCLUSION: This study highlights the importance of host genetic factors in vaccine responses. Furthermore, it supports the approach of studying the effect of combinations of multiple alleles, in haplotypes or in combinations of haplotypes, on complex phenotypes within a biological pathway.

Antibodies, Bacterial↗
PubMed2006

Functional polymorphisms in the mannan-binding lectin 2 gene: effect on MBL levels and otitis media.

BACKGROUND: Mannan-binding lectin (MBL) can bind to microorganisms, initiating the lectin pathway of complement activation. Aberrant MBL serum levels, caused by MBL2 gene polymorphisms, are a possible risk factor for recurrent infections. Within the 7 common MBL haplotypes, still considerable variation in MBL serum levels exists. OBJECTIVE: To investigate functional MBL levels and MBL2 polymorphisms in a large cohort of children with recurrent acute otitis media. METHODS: Twelve genetic variants in the MBL2 gene and functional MBL serum levels were determined in a cohort of children with recurrent acute otitis media. Haplotypes were constructed and associated with functional MBL serum levels and the number of otitis episodes in the previous year. RESULTS: The 7 common MBL2 haplotypes mainly determine the level of functional MBL in serum. In addition, the 3130G>C single nucleotide polymorphism, located in exon 4, further significantly influenced functional MBL levels within the LXPA haplotype. LXPA carriers with 3130G showed a significantly lower geometric mean functional MBL serum level of 0.19 mug/mL compared with 0.70 mug/mL in 3130C carriers (P = .026). Nonwild-type MBL2 carriers between 12 and 24 months had a significantly increased number of otitis episodes (5.1/y) compared with wild-type MBL2 carriers (4.1/y; P = .027). In older children, this association was not found anymore. CONCLUSION: Additional single nucleotide polymorphisms within the 7 common haplotypes can further explain the observed variation in functional MBL serum levels. MBL seems to be of particular clinical importance during early childhood, when maternally derived antibodies have waned, and protective adaptive immunity is not well developed yet. CLINICAL IMPLICATIONS: Single nucleotide polymorphisms in the promoter region, in exon 1, and in exon 4 of MBL2 contribute to increased risk for otitis media in children younger than 2 years.

Acute Disease↗
PubMed2006

Distinct cytokine and chemokine profiles in the aqueous of patients with uveitis and cystoid macular edema.

PURPOSE: To investigate the global cytokine and chemokine expression pattern in the aqueous humor of uveitis patients and relate them to clinical features. DESIGN: Cross-sectional study. METHODS: In 31 aqueous humor samples from uveitis patients, the concentration of mediators was measured by a multiplex immunoassay. Eleven control samples were included. RESULTS: Uveitis samples had higher levels of interleukin-6, interleukin-8, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule (sVCAM), and interferon-inducible protein-10 (IP-10) than nonuveitis controls. Active uveitis samples had higher levels of interleukin-6, interleukin-10, interferon-gamma, sVCAM, regulated on activation, normal T cell expressed and secreted (RANTES), and IP-10 than quiescent uveitis samples. Infectious uveitis was associated with higher levels of interleukin-10 than noninfectious uveitis (P < .03 for all subgroups). No significant differences were found between cystoid macular edema (CME) and non-CME samples. CONCLUSIONS: Elevated levels of specific mediators were found in active and in infectious uveitis, but not in CME. Mediator profiles might lead to a better understanding of the pathogenesis of uveitis.

Adult↗
PubMed2006

Solid-phase and bead-based cytokine immunoassay: a comparison.

Cytokines and chemoattractive cytokines (chemokines) are present in a wide variety of body fluids such as plasma, cerebrospinal fluid, bronchoaveolar fluid, amniotic fluid, synovial fluid, middle ear effusion fluid, and urine. Cytokines can be detected using classical solid-phase sandwich immunoassays such as enzyme-linked immunosorbent assay (ELISA) or with a bead based multiplex immunoassay (MIA). The physical chemical properties of the different body fluids (such as pH and total protein content) differ, which may have an impact on the outcome of the cytokine assay. Both ELISA as well as MIA cytokine detection systems are constructed by sandwiching the protein of interest between a capture and reporter antibody. When the biological sample contains heterophilic antibodies (such as in patients with auto-immune diseases), these non-specific antibodies can cause false positive results. During pathological conditions, cytokines may be found over a wide concentration range; likewise have to cover this dynamic range in a similar fashion. The correct (statistical) analysis of standard curves and (multiplexed) data are critical for proper interpretation. Classical ELISA based cytokine assays are robust, easy to use and very well suited for measurement of single cytokines. Due to an increased interest in the integral approach to understand biological processes (the omics era), multiplex immunoassays for detection of cytokines and the interpretation of these assays are gaining popularity.

Animals↗
PubMed2006

Long-term effects of pediatric adenotonsillectomy on serum immunoglobulin levels: results of a randomized controlled trial.

BACKGROUND: It remains controversial whether pediatric adenotonsillectomy ultimately results in decreased serum immunoglobulin levels and if so whether such a decrease is associated with increased susceptibility to upper respiratory tract infections (URIs). OBJECTIVE: To evaluate changes in serum immunoglobulin levels in relation to occurrence of URIs in children participating in a randomized controlled trial on the effectiveness of adenotonsillectomy. METHODS: A total of 300 children aged 2 to 8 years, with symptoms of recurrent throat infections or tonsillar hypertrophy, were randomly assigned to either adenotonsillectomy or watchful waiting (WW). Serum samples were collected at baseline and at 1-year follow-up. Occurrence of throat infections and other URIs during first-year follow-up was recorded in a diary by the child's parents. RESULTS: Paired serum samples were available for 123 children (63 in the adenotonsillectomy group and 60 in the WW group). IgG1 and IgG2 levels decreased but remained within the reference range for age in both study arms. IgM and IgA levels decreased as well but remained elevated. The IgA level in the adenotonsillectomy group decreased in significantly greater degree compared with the WW group, but this difference disappeared in cases where children experienced frequent URIs. In general, no relation between immunoglobulin levels and the number of throat infections or URIs at 1-year follow-up was found. CONCLUSIONS: Immunoglobulin levels of children undergoing adenotonsillectomy decreased from elevated to slightly elevated or reference values for age during 1-year follow-up irrespective of treatment (adenotonsillectomy or WW). IgA showed a greater decrease in the adenotonsillectomy group but rose to levels comparable with the WW group in cases of frequent URIs. This finding indicates that the remaining mucosa-associated lymphoid tissue can compensate for the loss of tonsil and adenoid tissue.

Adenoidectomy↗
PubMed2006

Inflammatory mediators for the diagnosis and treatment of sepsis in early infancy.

Interleukin-6 (IL-6), interleukin-8 (IL-8), and procalcitonin (PCT) are important parameters in the diagnosis of sepsis and for differentiating between viral and bacterial infection in children. We compared the value of IL-6, IL-8, and PCT with C-reactive protein (CRP) in the diagnosis and treatment of late-onset sepsis among infants admitted to the neonatal intensive care unit (group I) and febrile infants admitted to general hospitals from home (group II). Group I was divided into subgroups Ia, positive blood culture (all Gram-positive cocci); Ib, negative blood culture; and Ic, controls. Group II was divided into subgroups IIa, systemic enterovirus infection, and IIb, no enterovirus infection. Enterovirus was identified by real-time (RT) polymerase chain reaction (PCR) and/or by culture in blood and cerebrospinal fluid (CSF). The positive predictive values of IL-6, IL-8, and PCT (78%, 72%, and 83%, respectively) were better than that of CRP (63%) in the diagnosis of neonatal sepsis. After 48 h of antibiotic treatment, IL-6 and IL-8 levels significantly decreased and PCT stabilized in clinically recovered patients, suggesting that these markers may be useful in distinguishing patients in which antibiotic treatment may be discontinued. Among infants of subgroup IIa, 80%-90% had normal values of IL-6, IL-8, and PCT, whereas CRP was increased in 40%. In conclusion, IL-6, IL-8, and PCT are better parameters than CRP in the diagnosis and follow-up of neonatal sepsis due to coagulase-negative staphylococci (CoNS) and in the exclusion of bacterial infection among those with enteroviral infection among febrile infants presenting from home.

C-Reactive Protein↗
PubMed2006

Effect of combined pneumococcal conjugate and polysaccharide vaccination on recurrent otitis media with effusion.

BACKGROUND: Otitis media with effusion (OME) is very common during childhood. Because Streptococcus pneumoniae is one of the most common bacterial pathogens involved in OME, pneumococcal vaccines may have a role in the prevention of recurrent OME. OBJECTIVE: We sought to assess the effect of combined pneumococcal conjugate and polysaccharide vaccinations on the recurrence of OME. METHODS: A randomized, controlled trial was performed with 161 children, 2 to 8 years of age, with documented persistent bilateral OME. All subjects were treated with tympanostomy tubes (TTs). One half of the subjects were assigned randomly to additional vaccination with a 7-valent pneumococcal conjugate vaccine 3 to 4 weeks before and a 23-valent pneumococcal polysaccharide vaccine 3 months after tube insertion. Blood samples were drawn at the first vaccination, at the time of TT placement, and 1 and 3 months after the second vaccination. Levels of IgA and IgG serum antibody against the 7-valent pneumococcal conjugate vaccine serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F were measured with enzyme-linked immunosorbent assays. All children were monitored for recurrence of OME for 6 months after spontaneous extrusion of the TTs. RESULTS: The overall recurrence rate of bilateral OME was 50%. Pneumococcal vaccinations induced significant 4.6- to 24.4-fold increases in the geometric means of all conjugate vaccine serotype antibody titers but did not affect recurrence of OME. CONCLUSIONS: Combined pneumococcal conjugate and polysaccharide vaccination does not prevent recurrence of OME among children 2 to 8 years of age previously known to have persistent OME. Therefore, pneumococcal vaccines are not indicated for the treatment of children suffering from recurrent OME.

Child↗
PubMed2005

Pneumococcal conjugate vaccination in children with recurrent acute otitis media: a therapeutic alternative?

BACKGROUND: Based on two clinical trials in healthy infants the American Academy of Pediatrics (AAP) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media (AOM). OBJECTIVE: To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences, its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media. METHODS: In this double-blind, randomized study, 74 Belgian children, aged 1-7 years, with at least 2 clinically diagnosed episodes of acute otitis media in the previous year were enrolled. Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine. Total follow-up was 26 months. RESULTS: Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes, no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group (rate ratio: 1.16; 95% CI: 0.69-1.96). Overall nasopharyngeal pneumococcal carriage remained stable. However, a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination. CONCLUSION: Clinically no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM.

Acute Disease↗
PubMed2005

Pneumococcal vaccine efficacy for mucosal pneumococcal infections depends on Fcgamma receptor IIa polymorphism.

IgG2 antibodies are the main antibody subclass produced after pneumococcal polysaccharide vaccination. For these antibodies to be effective, interaction with FcgammaIIa receptors on phagocytic cells is necessary. FcgammaRIIa displays a functional polymorphism with either a histidine (H) or arginine (R) at position 131. Interaction of IgG2 antibodies depends on the H131 allele, whereas this interaction is low to absent with the R131 allele. We tested the clinical efficacy of combined pneumococcal conjugate and pneumococcal polysaccharide vaccination according to FcgammaIIa-H/R131 genotype in a randomized double blind placebo controlled vaccination trial in children with a history of acute otitis media. We found a decisive role for the FcgammaIIa-H/R131 polymorphism on the clinical vaccine efficacy of combined pneumococcal conjugate and polysaccharide vaccinations. RR homozygotes showed a significant increase in recurrence of acute otitis media after pneumococcal vaccinations. This cannot be explained by differences in the pneumococcal specific antibody response or differences in nasopharyngeal pneumococcal carriage, but may be explained by less efficient interaction of FcgammaRIIa with polysaccharide-induced IgG2 anti-pneumococcal antibodies in RR homozygotes. Our data show that the genetic make-up of individuals or populations under study should be considered while evaluating vaccine efficacy trials.

Alleles↗
PubMed2005

Eustachian tube function before recurrence of otitis media with effusion.

OBJECTIVE: To study the role of eustachian tube function in the development of recurrent otitis media with effusion (OME) in children treated with tympanostomy tubes for OME. DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received tympanostomy tubes for bilateral OME at study entry. MAIN OUTCOME MEASURE: Recurrence of OME within 6 months of tube extrusion. RESULTS: No statistically significant differences were present in eustachian tube function test results between ears that developed recurrent OME and those that did not. The difference in passive ventilatory function between ears with and without OME recurrence was 10 daPa (95% confidence interval, -24 to 43 daPa) for opening pressure and -3 daPa (95% confidence interval, -18 to 11 daPa) for closing pressure. The overall difference in the proportion of ears with and without OME recurrence that could not equilibrate positive and negative applied pressures was 12% (95% confidence interval, -2% to 26%). The proportions of ears with and without OME recurrence that induced negative pressure in the middle ear by forcefully sniffing were 22% and 31%, respectively (P = .75). CONCLUSION: Measurement of ventilatory and protective eustachian tube function using the forced response test, the pressure equilibration test, and the sniff test has no value in predicting whether children have an increased risk of OME recurrence.

Child, Preschool↗
PubMed2005

Immune status and eustachian tube function in recurrence of otitis media with effusion.

OBJECTIVE: To study the combined role of immune status and eustachian tube function in the development of recurrent bilateral otitis media with effusion (OME). DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of bilateral OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received bilateral tympanostomy tubes at study entry. MAIN OUTCOME MEASURE: Recurrence of bilateral OME within 6 months after tube extrusion. RESULTS: Univariate analyses of various immunologic factors (IgA, IgG1, IgG2, IgG3, IgG4, mannose-binding lectin, and the FcgammaRIIa-H/R131 genotype) and eustachian tube function (forced response test) did not show any significant associations with bilateral OME recurrence. Multivariate analyses showed that children with closing pressures higher than the 75th percentile and IgA or IgG2 levels below the 50th percentile of the cohort were more likely to develop recurrent OME than children with closing pressures higher than the 75th percentile and IgA or IgG2 levels above the 50th percentile. The corresponding risk ratios were 6.3 (95% confidence interval [CI], 1.0-40.1) for IgA level and 3.0 (95% CI, 1.1-8.2) for IgG2 level. The multivariate analyses also revealed that increasing serum levels of functional mannose-binding lectin were associated with decreasing probabilities of developing recurrent OME (odds ratio, 0.7; 95% CI, 0.6-1.0). CONCLUSION: Recurrence of bilateral OME after tympanostomy tube placement is more likely in children with a combination of low IgA or low IgG2 levels with poor eustachian tube function and decreased levels of mannose-binding lectin.

Antigens, CD↗
PubMed2005

Immunological status in the aetiology of recurrent otitis media with effusion: serum immunoglobulin levels, functional mannose-binding lectin and Fc receptor polymorphisms for IgG.

The objective was to study the role of serum immunoglobulin levels, mannose-binding lectin (MBL), and Fc gamma receptor (FcgammaR) polymorphisms on the development of recurrent otitis media with effusion (OME). Children aged between two and seven years with persisting OME received bilateral tympanostomy tubes and immunological parameters were investigated in relation with OME recurrence within six months after tube extrusion. No statistically significant differences in serum immunoglobulin levels were present between children with and without OME recurrence. In children with bilateral recurrence (n = 56), median levels of MBL were 1.39 mg/L compared to 2.48 mg/L in children with OME recurrence (n = 17) (p = 0.29). In addition, 34% of the children with bilateral recurrence were homozygous for the genotype FcgammaRIIa-R/R131, whereas less than 20% of the children with unilateral recurrence or those without recurrence were homozygous for this Fcgamma receptor (p = 0.26). Serum mannose-binding lectin and FcgammaRIIa-R/R131 polymorphism may play a role in the aetio-pathogenesis of recurrent OME.

Child↗
PubMed2005

Immunologic screening of children with recurrent otitis media.

Some 5% to 10% of all infants and toddlers suffer from four or more episodes of otitis per year. Usually, this is a temporary problem that resolves with increasing age. In a minority of cases, otitis episodes are frequent or have an abnormal course, with complications such as mastoiditis. In these cases, immunologic screening is indicated, to exclude an immunodeficiency. Agammaglobulinemia or hypogammaglobulinemia is rare among these patients. Other immune defects that occur more often are deficient or lowered immunoglobulin (Ig)A or decreased levels of one or more IgG subclass, in particular IgG2. The specific antibody response to bacterial capsular polysaccharides often is disturbed. These findings can give direction to the treatment of children with frequent, recurrent otitis.

Antibodies↗
PubMed2005

Disease modifying genes in cystic fibrosis.

The variation in cystic fibrosis (CF) lung disease and development of CF related complications correlates poorly with the genotype of the CF transmembrane regulator (CFTR) and with environmental factors. Increasing evidence suggests that phenotypic variation in CF can be attributed to genetic variation in genes other than the CFTR gene, so-called modifier genes. In recent years, multiple candidate modifier genes have been investigated in CF, especially genes that are involved in the control of infection, immunity and inflammation. Some of these genes have been rather conclusively identified as modifiers of the CF phenotype, whereas associations found in other genes have not been confirmed or are conflicting. Identification of genetic variation in modifier genes, obtained by genotype-phenotype studies in well-defined patient populations, may be used as an aid to prognosis and may provide the possibility of new therapeutic interventions.

Cystic Fibrosis↗
PubMed2005

Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies.

Cytokines, chemokines and soluble adhesion molecules interact in a complex network within the immune system. Fingerprinting of these proteins may allow the use of these proteins as biomarkers for identification of disease, disease subtyping and monitoring therapeutic interventions. We developed a multiplex immunoassay (MIA) for the detection of 30 proteins in a variety of human body fluids such as plasma and synovial fluid (SF). The measurement of these proteins is hampered by the presence of human (auto-) antibodies, which can cause non-specific binding. We have validated a novel approach for the removal of interfering immunoglobulins using pre-absorption with protein-L. Interfering (auto-) antibodies, such as rheumatoid factor (RF), were removed using three methods; polyethylene glycol (PEG) precipitation, pre-absorption with human gamma-globulin or pre-absorption with protein-L. A significant decrease of RF was observed after a 2 h incubation with protein-L. RF IgM levels were reduced by 89% whereas total IgM, IgG and IgA levels were reduced by 60%. Residual immunoglobulins were blocked with rodent serum and did not interfere with the multiplex immunoassay. Comparing the MIA with a conventional enzyme-linked immunosorbent assay (ELISA) using a panel of spiked plasma samples resulted in correlation coefficients for all mediators between R2 = 0.88 and R2 = 0.99. Intra-assay variance was less than 10% whereas inter-assay variance ranged between 6% and 16%. Pathological samples with heterophilic antibodies hamper immunoassays such as ELISA and MIA. We show that pre-absorption with protein-L is a powerful tool for removal of interfering immunoglobulins from human bodily fluids to be used in immunoassays for studying changes in protein patterns.

Antibodies, Heterophile↗
PubMed2005

A novel human CD32 mAb blocks experimental immune haemolytic anaemia in FcgammaRIIA transgenic mice.

A fully human IgG1 kappa antibody (MDE-8) was generated, which recognised Fc-gamma receptor IIa (FcgammaRIIa) molecules on CD32 transfectants, peripheral blood monocytes, polymorphonuclear cells and platelets. This antibody blocked FcgammaRIIa ligand-binding via its F(ab')(2) fragment. Overnight incubation of monocytes with F(ab')(2) fragments of MDE-8 leads to a c. 60% decrease in cell surface expression of FcgammaRIIa. MDE-8 whole antibody induced a concomitant c. 30% decrease of FcgammaRI on THP-1 cells and monocytes. In humans FcgammaRIIa plays an important role in the clearance of antibody-coated red blood cells in vivo. As an equivalent of FcgammaRIIa does not exist in mice, the in vivo effect of MDE-8 was studied in an FcgammaRIIa transgenic mouse model. In these mice, antibody-induced anaemia could readily be blocked by MDE-8. These data document a new human antibody that effectively blocks FcgammaRIIa, induces modulation of both FcgammaRIIa and FcgammaRI from phagocytic cells, and ameliorates antibody-induced anaemia in vivo.

Anemia, Hemolytic, Autoimmune↗