Publications by authors named "Selma P Wiertsema"

31 Publications

The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies.

Nutrients 2021 Mar 9;13(3). Epub 2021 Mar 9.

Danone Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.

Infectious diseases and infections remain a leading cause of death in low-income countries and a major risk to vulnerable groups, such as infants and the elderly. The immune system plays a crucial role in the susceptibility, persistence, and clearance of these infections. With 70-80% of immune cells being present in the gut, there is an intricate interplay between the intestinal microbiota, the intestinal epithelial layer, and the local mucosal immune system. In addition to the local mucosal immune responses in the gut, it is increasingly recognized that the gut microbiome also affects systemic immunity. Clinicians are more and more using the increased knowledge about these complex interactions between the immune system, the gut microbiome, and human pathogens. The now well-recognized impact of nutrition on the composition of the gut microbiota and the immune system elucidates the role nutrition can play in improving health. This review describes the mechanisms involved in maintaining the intricate balance between the microbiota, gut health, the local immune response, and systemic immunity, linking this to infectious diseases throughout life, and highlights the impact of nutrition in infectious disease prevention and treatment.
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http://dx.doi.org/10.3390/nu13030886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001875PMC
March 2021

Free Amino Acids in Human Milk: A Potential Role for Glutamine and Glutamate in the Protection Against Neonatal Allergies and Infections.

Front Immunol 2020 28;11:1007. Epub 2020 May 28.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

Breastfeeding is indicated to support neonatal immune development and to protect against neonatal infections and allergies. Human milk composition is widely studied in relation to these unique abilities, which has led to the identification of various immunomodulating components in human milk, including various bioactive proteins. In addition to proteins, human milk contains free amino acids (FAAs), which have not been well-studied. Of those, the FAAs glutamate and glutamine are by far the most abundant. Levels of these FAAs in human milk sharply increase during the first months of lactation, in contrast to most other FAAs. These unique dynamics are globally consistent, suggesting that their levels in human milk are tightly regulated throughout lactation and, consequently, that they might have specific roles in the developing neonate. Interestingly, free glutamine and glutamate are reported to exhibit immunomodulating capacities, indicating that these FAAs could contribute to neonatal immune development and to the unique protective effects of breastfeeding. This review describes the current understanding of the FAA composition in human milk. Moreover, it provides an overview of the effects of free glutamine and glutamate on immune parameters relevant for allergic sensitization and infections in early life. The data reviewed provide rationale to study the role of free glutamine and glutamate in human milk in the protection against neonatal allergies and infections.
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http://dx.doi.org/10.3389/fimmu.2020.01007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270293PMC
May 2021

A free amino acid-based diet partially prevents symptoms of cow's milk allergy in mice after oral sensitization with whey.

Immun Inflamm Dis 2020 03 7;8(1):93-105. Epub 2020 Feb 7.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

Background: Amino acid-based formulas (AAFs) are used for the dietary management of cow's milk allergy (CMA). Whether AAFs have the potential to prevent the development and/or symptoms of CMA is not known.

Objective: The present study evaluated the preventive effects of an amino acid (AA)-based diet on allergic sensitization and symptoms of CMA in mice and aimed to provide insight into the underlying mechanism.

Methods: C3H/HeOuJ mice were sensitized with whey protein or with phosphate-buffered saline as sham-sensitized control. Starting 2 weeks before sensitization, mice were fed with either a protein-based diet or an AA-based diet with an AA composition based on that of the AAF Neocate, a commercially available AAF prescribed for the dietary management of CMA. Upon challenge, allergic symptoms, mast cell degranulation, whey-specific immunoglobulin levels, and FoxP3 cell counts in jejunum sections were assessed.

Results: Compared to mice fed with the protein-based diet, AA-fed mice had significantly lower acute allergic skin responses. Moreover, the AA-based diet prevented the whey-induced symptoms of anaphylaxis and drop in body temperature. Whereas the AA-based diet had no effect on the levels of serum IgE and mucosal mast cell protease-1 (mMCP-1), AA-fed mice had significantly lower serum IgG2a levels and tended to have lower IgG1 levels (P = .076). In addition, the AA-based diet prevented the whey-induced decrease in FoxP3 cells. In sham-sensitized mice, no differences between the two diets were observed in any of the tested parameters.

Conclusion: This study demonstrates that an AA-based diet can at least partially prevent allergic symptoms of CMA in mice. Differences in FoxP3 cell counts and serum levels of IgG2a and IgG1 may suggest enhanced anti-inflammatory and tolerizing capacities in AA-fed mice. This, combined with the absence of effects in sham-sensitized mice indicates that AAFs for the prevention of food allergies may be an interesting concept that warrants further research.
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http://dx.doi.org/10.1002/iid3.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016843PMC
March 2020

High concentrations of middle ear antimicrobial peptides and proteins and proinflammatory cytokines are associated with detection of middle ear pathogens in children with recurrent acute otitis media.

PLoS One 2019 26;14(12):e0227080. Epub 2019 Dec 26.

Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.

Recurrent and chronic otitis media (OM) are often refractory to antibiotics due to bacterial persistence in biofilm within the middle ear. In vitro and in vivo studies have demonstrated that antimicrobial proteins and peptides (AMPs) are bactericidal against otopathogens, indicating potential therapeutic value for recalcitrant OM. We measured concentrations of 6 AMPs and 14 cytokines in middle ear effusion (MEE) from 67 children undergoing ventilation tube insertion for recurrent acute OM. Sixty one percent of children had bacterial otopathogens detected in their MEE, 39% by PCR and 22% by PCR and culture. Groups were defined as: PCR-negative/culture-negative (absence of bacterial otopathogen), n = 26; PCR-positive/culture-negative (presence of nonculturable bacterial otopathogen), n = 26; PCR-positive/culture-positive (presence of culturable bacterial otopathogen), n = 15. Age, antibiotic usage, day-care attendance, presence of respiratory viruses in MEE and number of AOM episodes were similar between groups. AMP and cytokine concentrations were higher in children with bacterial otopathogens in their MEE compared to those with no bacterial otopathogens. Median concentrations of AMPs (except HBD2) were 3 to 56-fold higher in MEE from children with bacterial otopathogens detected in their MEE (P ≤ 0.01). Similarly, median cytokine concentrations (except TGFβ) were >16-fold higher in MEE with bacterial otopathogens detected (P ≤ 0.001). This is the first study to measure AMPs in MEE and together with the cytokine data, results suggest that elevated AMPs and cytokines in MEE are a marker of inflammation and bacterial persistence. AMPs may play an important role in OM pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227080PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932785PMC
April 2020

Bacterial Reservoirs in the Middle Ear of Otitis-prone Children Are Associated With Repeat Ventilation Tube Insertion.

Pediatr Infect Dis J 2020 02;39(2):91-96

From the Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.

Background: Repeat ventilation tube insertion (VTI) is common in children with recurrent acute otitis media (rAOM). Identifying risk factors associated with repeat surgery will improve clinical management and prevent repeat VTI.

Methods: Surgical records were assessed at 8 years following VTI surgery for rAOM in children 6-36 months of age. Children were grouped according to detection of bacterial otopathogen in their middle ear effusion (MEE) at the time of VTI, and outcomes for future otorhinolaryngology surgery compared.

Results: Age, gender, pneumococcal vaccination status, antibiotic usage, day-care attendance, number of siblings and number of AOM episodes were similar between groups. Of the 63 children who had PCR +ve MEE, 58.7% required repeat VTI compared with 31.4% of the 51 children with no otopathogen detected in their MEE (odds ratio = 3.1, 95% confidence interval [1.4-6.8]; P = 0.004). Nontypeable Haemophilus influenzae (NTHi) was the predominant otopathogen in MEE (79% of all PCR +ve MEE). Respiratory virus detection was not associated with repeat VTI.

Conclusions: Presence of bacterial otopathogen, specifically nontypeable H. influenzae, in the middle ear during VTI was a predictor of children at-risk of repeat VTI. Here, we identify a modifiable microbiologic factor for repeat VTI that can be targeted to improve clinical management of rAOM.
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http://dx.doi.org/10.1097/INF.0000000000002541DOI Listing
February 2020

Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens.

Clin Vaccine Immunol 2017 Apr 5;24(4). Epub 2017 Apr 5.

School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia.

Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations.
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http://dx.doi.org/10.1128/CVI.00556-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382827PMC
April 2017

Otitis-Prone Children Produce Functional Antibodies to Pneumolysin and Pneumococcal Polysaccharides.

Clin Vaccine Immunol 2017 Mar 6;24(3). Epub 2017 Mar 6.

School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.

The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone and healthy children have similar antibody titers to pneumococcal proteins and polysaccharides (vaccine and nonvaccine types); however, the quality of antibodies from otitis-prone children has not been investigated. Antibody function, rather than titer, is considered to be a better correlate of protection from pneumococcal disease. Therefore, we compared the capacities of antibodies from otitis-prone (cases) and healthy (controls) children to neutralize pneumolysin, the pneumococcal toxin currently in development as a vaccine antigen, and to opsonize pneumococcal vaccine and nonvaccine serotypes. A pneumolysin neutralization assay was conducted on cholesterol-depleted complement-inactivated sera from 165 cases and 61 controls. A multiplex opsonophagocytosis assay (MOPA) was conducted on sera from 20 cases and 20 controls. Neutralizing and opsonizing titers were calculated with antigen-specific IgG titers to determine antibody potency for pneumolysin, pneumococcal conjugate vaccine (PCV) polysaccharides, and non-PCV polysaccharides. There was no significant difference in antibody potencies between cases and controls for the antigens tested. Antipneumolysin neutralizing titers increased with the number of episodes of acute OM, but antibody potency did not. Pneumolysin antibody potency was lower in children colonized with pneumococci than in noncarriers, and this was significant for the otitis-prone group ( < 0.05). The production of functional antipneumococcal antibodies in otitis-prone children demonstrates that they respond to the current PCV and are likely to respond to pneumolysin-based vaccines as effectively as healthy children.
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http://dx.doi.org/10.1128/CVI.00497-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339643PMC
March 2017

A practical method for preparation of pneumococcal and nontypeable Haemophilus influenzae inocula that preserves viability and immunostimulatory activity.

BMC Res Notes 2013 Dec 9;6:522. Epub 2013 Dec 9.

School of Paediatrics and Child Health, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia.

Background: Convenience is a major reason for using killed preparations of bacteria to investigate host-pathogen interactions, however, host responses to such preparations can result in different outcomes when compared to live bacterial stimulation. We investigated whether cryopreservation of Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) permitted investigation of host responses to infection without the complications of working with freshly prepared live bacteria on the day of experimental challenge.

Findings: S. pneumoniae and NTHi retained >90% viability following cryopreservation in fetal calf serum for at least 8 weeks. Host responses to live, cryopreserved (1 week and 4 weeks), heat-killed or ethanol-killed S. pneumoniae and NTHi were assessed by measuring cytokine release from stimulated peripheral blood mononuclear cells (PBMCs). We found that cryopreserved bacteria, in contrast to heat-killed and ethanol-killed preparations, resulted in comparable levels of inflammatory cytokine release from PBMCs when compared with fresh live bacterial cultures.

Conclusion: Cryopreservation of S. pneumoniae and NTHi does not alter the immunostimulatory properties of these species thereby enabling reproducible and biologically relevant analysis of host responses to infection. This method also facilitates the analysis of multiple strains on the same day and allows predetermination of culture purity and challenge dose.
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http://dx.doi.org/10.1186/1756-0500-6-522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867214PMC
December 2013

Genetic and functional evidence for a role for SLC11A1 in susceptibility to otitis media in early childhood in a Western Australian population.

Infect Genet Evol 2013 Jun 26;16:411-8. Epub 2013 Mar 26.

Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia.

Otitis media (OM) is a common disease in early childhood characterised by inflammation of the middle ear. Susceptibility to recurrent acute OM (rAOM; ≥3 episodes AOM in 6 months) and chronic OM with effusion (COME; middle ear effusion ≥3 months) is 40-70% heritable. Three bacterial pathogens commonly associated with OM, Streptococcus pneumoniae (Sp), non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mc), have been observed within adenoids and as facultative intracellular pathogens that invade and survive in mononuclear cells. Case/pseudo-control conditional logistic regression analysis of variants in the SLC11A1 gene, initially identified for its role in resistance to intra-macrophage pathogens in mice, revealed association with OM at four polymorphisms (Pbest=0.025) in 531 families (660 affected children) from the Western Australian Family Study of Otitis Media. This included association at the functional promoter GTn polymorphism (rs34448891) with alleles that regulate high (allele 3; odds ratio=1.2, 95% CI 1.00-1.44, P=0.04) versus low (allele 2; odds ratio=0.83, 95% CI 0.69-0.99, P=0.04) SLC11A1 expression. Haplotype and stepwise conditional logistic regression analyses support a single genetic effect in the proximal region of SLC11A1, with the haplotype 3_C_C_G across rs34448891_rs2276631_rs3731865_rs2695343 significantly (P=0.008) over-transmitted to affected offspring. Stratified analysis showed no association with OM in children who had undergone adenoidectomy (296 children), whereas children with adenoids intact (364 children) showed improved significance at the GTn polymorphism (allele 3: odds ratio=1.38, 95% CI=1.10-1.75, P=0.006). Quantitative RT/PCR demonstrated high expression of SLC11A1 in mononuclear cells isolated from adenoid tissue, with a trend for decreased expression with increasing copies of GTn allele 2. Expression of SLC11A1 was enhanced at 12 (P=1.2×10(-3)) and 24h (P<1.0×10(-4)) after infection of Mono-Mac-6 cells with NTHi. This study identifies SLC11A1 as a novel candidate for OM susceptibility, particularly in children with adenoids intact. Further analysis in other cohorts is required to validate these observations.
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http://dx.doi.org/10.1016/j.meegid.2013.03.023DOI Listing
June 2013

Neutrophil extracellular traps and bacterial biofilms in middle ear effusion of children with recurrent acute otitis media--a potential treatment target.

PLoS One 2013 5;8(2):e53837. Epub 2013 Feb 5.

School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia.

Background: Bacteria persist within biofilms on the middle ear mucosa of children with recurrent and chronic otitis media however the mechanisms by which these develop remain to be elucidated. Biopsies can be difficult to obtain from children and their small size limits analysis.

Methods: In this study we aimed to investigate biofilm presence in middle ear effusion (MEE) from children with recurrent acute otitis media (rAOM) and to determine if these may represent infectious reservoirs similarly to those on the mucosa. We examined this through culture, viability staining and fluorescent in situ hybridisation (FISH) to determine bacterial species present. Most MEEs had live bacteria present using viability staining (32/36) and all effusions had bacteria present using the universal FISH probe (26/26). Of these, 70% contained 2 or more otopathogenic species. Extensive DNA stranding was also present. This DNA was largely host derived, representing neutrophil extracellular traps (NETs) within which live bacteria in biofilm formations were present. When treated with the recombinant human deoxyribonuclease 1, Dornase alfa, these strands were observed to fragment.

Conclusions: Bacterial biofilms, composed of multiple live otopathogenic species can be demonstrated in the MEEs of children with rAOM and that these contain extensive DNA stranding from NETs. The NETs contribute to the viscosity of the effusion, potentially contributing to its failure to clear as well as biofilm development. Our data indicates that Dornase alfa can fragment these strands and may play a role in future chronic OM treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053837PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564866PMC
August 2013

High pneumococcal serotype specific IgG, IgG1 and IgG2 levels in serum and the middle ear of children with recurrent acute otitis media receiving ventilation tubes.

Vaccine 2013 Feb 9;31(10):1393-9. Epub 2013 Jan 9.

Telethon Institute for Child Health Research, Centre for Child Health Research, 100 Roberts Road, Perth, WA 6008, Australia.

Recurrent acute otitis media (AOM), frequently caused by Streptococcus pneumoniae, is a major paediatric health problem. A reduced antibody response against pneumococcal polysaccharides may contribute to an increased susceptibility to AOM. Using a multiplex bead-based assay we measured IgG, IgG1 and IgG2 levels against 11 pneumococcal polysaccharides in serum samples from 166 children below 3 years of age with a history of at least 3 episodes of acute otitis media receiving ventilation tubes, and 61 healthy controls. Pneumococcal serotype specific IgG was also determined in 144 middle ear effusion samples. Pneumococcal serotype specific IgG, IgG1 and IgG2 levels were similar in children with or without AOM, except for IgG and IgG1 levels against serotype 5, which were significantly higher in children with a history of frequent AOM (IgG: 137.5 μg/ml vs. 84.0 μg/ml; p=0.02; IgG1: 24.5 μg/ml vs. 18.2 μg/ml; p=0.05). The age-related development of pneumococcal serotype-specific IgG, IgG1 and IgG2 levels was similar in children with or without a history of AOM. Pneumococcal serotype specific IgG was present in middle ear effusion and these levels correlated significantly with serum titres. Children with a history of frequent AOM receiving ventilation tubes do not have a deficient IgG, IgG1 or IgG2 response against pneumococcal polysaccharides, either induced by vaccination or due to natural exposure. The strong correlation between IgG levels in serum and the middle ear suggests parenteral pneumococcal conjugate vaccination induces antibodies in the middle ear which may therefore contribute to reducing the burden of AOM.
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http://dx.doi.org/10.1016/j.vaccine.2012.12.078DOI Listing
February 2013

New findings in the pathogenesis of otitis media.

Laryngoscope 2012 Dec;122 Suppl 4:S61-2

Princess Margaret Hospital for Children, Perth, Australia.

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http://dx.doi.org/10.1002/lary.23817DOI Listing
December 2012

IgG responses to Pneumococcal and Haemophilus influenzae protein antigens are not impaired in children with a history of recurrent acute otitis media.

PLoS One 2012 12;7(11):e49061. Epub 2012 Nov 12.

School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.

Background: Vaccines including conserved antigens from Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) have the potential to reduce the burden of acute otitis media. Little is known about the antibody response to such antigens in young children with recurrent acute otitis media, however, it has been suggested antibody production may be impaired in these children.

Methods: We measured serum IgG levels against 4 pneumococcal (PspA1, PspA 2, CbpA and Ply) and 3 NTHi (P4, P6 and PD) proteins in a cross-sectional study of 172 children under 3 years of age with a history of recurrent acute otitis media (median 7 episodes, requiring ventilation tube insertion) and 63 healthy age-matched controls, using a newly developed multiplex bead assay.

Results: Children with a history of recurrent acute otitis media had significantly higher geometric mean serum IgG levels against NTHi proteins P4, P6 and PD compared with healthy controls, whereas there was no difference in antibody levels against pneumococcal protein antigens. In both children with and without a history of acute otitis media, antibody levels increased with age and were significantly higher in children colonised with S. pneumoniae or NTHi compared with children that were not colonised.

Conclusions: Proteins from S. pneumoniae and NTHi induce serum IgG in children with a history of acute otitis media. The mechanisms in which proteins induce immunity and potential protection requires further investigation but the dogma of impaired antibody responses in children with recurrent acute otitis media should be reconsidered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495775PMC
May 2013

Molecular surveillance of true nontypeable Haemophilus influenzae: an evaluation of PCR screening assays.

PLoS One 2012 28;7(3):e34083. Epub 2012 Mar 28.

Menzies School of Health Research, Charles Darwin University, Darwin, Australia.

Background: Unambiguous identification of nontypeable Haemophilus influenzae (NTHi) is not possible by conventional microbiology. Molecular characterisation of phenotypically defined NTHi isolates suggests that up to 40% are Haemophilus haemolyticus (Hh); however, the genetic similarity of NTHi and Hh limits the power of simple molecular techniques such as PCR for species discrimination.

Methodology/principal Findings: Here we assess the ability of previously published and novel PCR-based assays to identify true NTHi. Sixty phenotypic NTHi isolates, classified by a dual 16S rRNA gene PCR algorithm as NTHi (n = 22), Hh (n = 27) or equivocal (n = 11), were further characterised by sequencing of the 16S rRNA and recA genes then interrogated by PCR-based assays targeting the omp P2, omp P6, lgtC, hpd, 16S rRNA, fucK and iga genes. The sequencing data and PCR results were used to define NTHi for this study. Two hpd real time PCR assays (hpd#1 and hpd#3) and the conventional iga PCR assay were equally efficient at differentiating study-defined NTHi from Hh, each with a receiver operator characteristic curve area of 0.90 [0.83; 0.98]. The hpd#1 and hpd#3 assays were completely specific against a panel of common respiratory bacteria, unlike the iga PCR, and the hpd#3 assay was able to detect below 10 copies per reaction.

Conclusions/significance: Our data suggest an evolutionary continuum between NTHi and Hh and therefore no single gene target could completely differentiate NTHi from Hh. The hpd#3 real time PCR assay proved to be the superior method for discrimination of NTHi from closely related Haemophilus species with the added potential for quantification of H. influenzae directly from specimens. We suggest the hpd#3 assay would be suitable for routine NTHi surveillance and to assess the impact of antibiotics and vaccines, on H. influenzae carriage rates, carriage density, and disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314702PMC
August 2012

Children with otitis media mount a pneumococcal serotype specific serum IgG and IgA response comparable to healthy controls after pneumococcal conjugate vaccination.

Vaccine 2012 Apr 8;30(20):3136-44. Epub 2012 Feb 8.

School of Paediatrics and Child Health, The University of Western Australia, WA 6009, Perth, Australia.

It has been suggested that otitis-prone children have an impaired antibody response. To investigate this in the context of pneumococcal vaccination, we used a multiplex bead-based assay to measure serum IgG and IgA levels against pneumococcal serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7; serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) and 4 non-PCV7 serotypes (1, 5, 7F and 19A) in healthy (n=43) and otitis-prone children (n=75) before, 6 weeks after and 1 year after vaccination with one dose of PCV7. Pre-vaccination, otitis-prone children had significantly higher serum IgG levels against serotypes 4, 9V and 23F and against all non-PCV7 serotypes. One year following vaccination, there was no difference in IgG or IgA levels between healthy and otitis-prone children. The effect of the administration of one or two doses of PCV7 was investigated in otitis-prone children. After a second dose of PCV7, pneumococcal serotype specific IgG levels, but not IgA titres, were higher compared to the levels measured after the initial dose of PCV7. One year post PCV7 vaccination there was no difference in either IgG or IgA antibody levels to any of the PCV7 serotypes between children who received either one or two doses of PCV7. The finding that otitis-prone children do not have an impaired pneumococcal serotype-specific serum IgG or IgA response suggests that new pneumococcal conjugate vaccines may be immunogenic in otitis-prone children, however, further investigations are necessary to determine the clinical impact of such vaccines against the development of recurrent acute otitis media.
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http://dx.doi.org/10.1016/j.vaccine.2012.01.086DOI Listing
April 2012

Multi-species bacterial biofilm and intracellular infection in otitis media.

BMC Pediatr 2011 Oct 24;11:94. Epub 2011 Oct 24.

School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia.

Background: Bacteria which are metabolically active yet unable to be cultured and eradicated by antibiotic treatment are present in the middle ear effusion of children with chronic otitis media with effusion (COME) and recurrent acute otitis media (rAOM). These observations are suggestive of biofilm presence or intracellular sequestration of bacteria and may play a role in OM pathogenesis. The aim of this project is to provide evidence for the presence of otopathogenic bacteria intracellularly or within biofilm in the middle ear mucosa of children with COME or rAOM.

Methods: Middle ear mucosal biopsies from 20 children with COME or rAOM were examined for otopathogenic bacteria (either in biofilm or located intracellularly) using transmission electron microscopy (TEM) or species specific fluorescent in situ hybridisation (FISH) and confocal laser scanning microscopy (CLSM). One healthy control biopsy from a child undergoing cochlear implant surgery was also examined.

Results: No bacteria were observed in the healthy control sample. In 2 of the 3 biopsies imaged using TEM, bacteria were observed in mucus containing vacuoles within epithelial cells. Bacterial species within these could not be identified and biofilm was not observed. Using FISH with CLSM, bacteria were seen in 15 of the 17 otitis media mucosal specimens. In this group, 11 (65%) of the 17 middle ear mucosal biopsies showed evidence of bacterial biofilm and 12 demonstrated intracellular bacteria. 52% of biopsies were positive for both biofilm and intracellular bacteria. At least one otopathogen was identified in 13 of the 15 samples where bacteria were present. No differences were observed between biopsies from children with COME and those with rAOM.

Conclusion: Using FISH and CLSM, bacterial biofilm and intracellular infection with known otopathogens are demonstrated on/in the middle ear mucosa of children with COME and/or rAOM. While their role in disease pathogenesis remains to be determined, this previously undescribed infection pattern may help explain the ineffectiveness of current treatment strategies at preventing or resolving COME or rAOM.
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http://dx.doi.org/10.1186/1471-2431-11-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224757PMC
October 2011

High detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media.

J Med Virol 2011 Nov;83(11):2008-17

School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.

Both bacteria and viruses play a role in the development of acute otitis media, however, the importance of specific viruses is unclear. In this study molecular methods were used to determine the presence of nucleic acids of human rhinoviruses (HRV; types A, B, and C), respiratory syncytial viruses (RSV; types A and B), bocavirus (HBoV), adenovirus, enterovirus, coronaviruses (229E, HKU1, NL63, and OC43), influenza viruses (types A, B, and C), parainfluenza viruses (types 1, 2, 3, 4A, and 4B), human metapneumovirus, and polyomaviruses (KI and WU) in the nasopharynx of children between 6 and 36 months of age either with (n = 180) or without (n = 66) a history of recurrent acute otitis media and in 238 middle ear effusion samples collected from 143 children with recurrent acute otitis media. The co-detection of these viruses with Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis was analyzed. HRV (58.3% vs. 42.4%), HBoV (52.2% vs. 19.7%), polyomaviruses (36.1% vs. 15.2%), parainfluenza viruses (29.4% vs. 9.1%), adenovirus (25.0% vs. 6.1%), and RSV (27.8% vs. 9.1%) were detected significantly more often in the nasopharynx of children with a history of recurrent acute otitis media compared to healthy children. HRV was predominant in the middle ear and detected in middle ear effusion of 46% of children. Since respiratory viruses were detected frequently in the nasopharynx of both children with and without a history of recurrent acute otitis media, the etiological role of specific viruses in recurrent acute otitis media remains uncertain, however, anti-viral therapies may be beneficial in future treatment and prevention strategies for acute otitis media.
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http://dx.doi.org/10.1002/jmv.22221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166877PMC
November 2011

Predominance of nontypeable Haemophilus influenzae in children with otitis media following introduction of a 3+0 pneumococcal conjugate vaccine schedule.

Vaccine 2011 Jul 27;29(32):5163-70. Epub 2011 May 27.

School of Paediatrics and Child Health, The University of Western Australia, 35 Stirling Highway, WA 6009, Perth, Australia.

In Australia the 7-valent pneumococcal conjugate vaccine (PCV7) is administered at 2, 4 and 6 months of age, with no booster dose. Information on bacterial carriage and the aetiology of recurrent acute otitis media (rAOM) after introduction of PCV7 using the 3+0 schedule is required to evaluate the potential impact of second generation pneumococcal vaccines. We found that 2-4 years after introduction of PCV7 in the National Immunisation Program, nontypeable Haemophilus influenzae (NTHi) was the predominant pathogen isolated from the nasopharynx and middle ear of children with a history of rAOM. Compared with healthy controls (n=81), NTHi and Streptococcus pneumoniae carriage rates were significantly higher in children with a history of rAOM (n=186) (19% vs. 56% p<0.0001 and 26% vs. 41%, p=0.02, respectively). Carriage of PCV7 pneumococcal serotypes was rare, whereas PCV7-related and non-PCV7 serotypes were isolated of 38% of cases and 24% of controls. Serotype 19A was the most common serotype isolated from the nasopharynx and middle ear and accounted for 36% (14/39) of total pneumococcal isolates with reduced susceptibility to cotrimoxazole. Of the 119 children carrying NTHi, 17% of isolates were β-lactamase positive. The scarcity of PCV7 serotypes in children with and without a history of rAOM indicates that the 3+0 PCV7 schedule is preventing carriage and rAOM from PCV7 serotypes. Introduction of new vaccines in Australia with increased pneumococcal serotype and pathogen coverage, including 19A and NTHi, should decrease the circulation of antibiotic-resistant bacteria and reduce the burden of rAOM.
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http://dx.doi.org/10.1016/j.vaccine.2011.05.035DOI Listing
July 2011

Nasopharyngeal carriage of Haemophilus haemolyticus in otitis-prone and healthy children.

J Clin Microbiol 2010 Jul 12;48(7):2557-9. Epub 2010 May 12.

School of Paediatrics and Child Health, The University of Western Australia, Subiaco, Western Australia, Australia.

Haemophilus haemolyticus is often incorrectly categorized as nontypeable Haemophilus influenzae (NTHI) upon culture. PCR analyses of 266 NTHI-like nasopharyngeal isolates from children with and without recurrent acute otitis media (rAOM) revealed that 11.7% were H. haemolyticus and 9.4% gave equivocal results. Children with rAOM were more likely to carry H. haemolyticus.
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http://dx.doi.org/10.1128/JCM.00069-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897511PMC
July 2010

Theories of otitis media pathogenesis, with a focus on Indigenous children.

Med J Aust 2009 11;191(S9):S50-4

School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.

Otitis media is a common childhood illness associated with hearing loss, social disadvantage and medical costs. Prevalence and severity are high among Indigenous children. Respiratory bacterial and viral pathogens ascend the eustachian tube from the nasopharynx to the middle ear, causing inflammation, fluid accumulation, and bulging of the tympanic membrane, with or without pain. Among Australian Indigenous children, ear disease commences earlier in life, and involves multiple strains of bacterial pathogens at high density that persist longer. Persistent nasal discharge, overcrowded living conditions (particularly exposure to many children) and poor facilities for washing children perpetuate a vicious cycle of transmission and infection. Risk factors include environmental tobacco smoke, season, lack of breastfeeding, younger age and immature immune system, and possibly genetic factors. The innate immune system is a critical first response to infection, particularly as passive maternal antibodies decline and during the maturation of the infant adaptive immune response. The relative contributions of innate factors to protection from otitis media are currently not well understood. A diversity of antibodies that target strain-specific and conserved antigens are generated in response to natural exposure to otitis media pathogens (or to vaccines). Deficiencies in these antibodies may explain susceptibility to recurrent infections. Incremental contributions from all these elements are likely to be important in otitis media susceptibility versus protection. Effective medical and social strategies to prevent early age of onset are urgently needed.
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http://dx.doi.org/10.5694/j.1326-5377.2009.tb02927.xDOI Listing
November 2009

Genetic polymorphisms in immunoresponse genes TNFA, IL6, IL10, and TLR4 are associated with recurrent acute otitis media.

Pediatrics 2007 Oct;120(4):814-23

Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center, Dr Molewaterplein 50, Room Ee15-02, 3015 GE, Rotterdam, The Netherlands.

Objective: Cytokines and other inflammatory mediators are involved in the pathogenesis of otitis media. We hypothesized that polymorphisms in inflammatory response genes contribute to the increased susceptibility to acute otitis media in otitis-prone children.

Patients And Methods: DNA samples from 348 children with > or = 2 acute otitis media episodes, who were participating in a randomized, controlled vaccination trial, and 463 healthy adult controls were included. Polymorphisms in TNFA, IL1B, IL4, IL6, IL10, IL8, NOS2A, C1INH, PARP, TLR2, and TLR4 were genotyped. Genotype distributions in children with recurrent acute otitis media were compared with those in controls. Within the patient group, the number of acute otitis media episodes before vaccination and the clinical and immunologic response to pneumococcal conjugate vaccinations were analyzed.

Results: The IL6-174 G/G genotype was overrepresented in children with acute otitis media when compared with controls. In the patient group, TNFA promoter genotypes -238 G/G and -376 G/G and the TLR4 299 A/A genotype were associated with an otitis-prone condition. Furthermore, lower specific anticapsular antibody production after complete vaccination was observed in patients with the TNFA-238 G/G genotype or TNFA-863 A allele carriage. Finally, the IL10-1082 A/A genotype contributed to protection from the recurrence of acute otitis media after pneumococcal vaccination.

Conclusions: Variation in innate immunoresponse genes such as TNFA-863A, TNFA-376G, TNFA-238G, IL10-1082 A, and IL6-174G alleles in the promoter sequences may result in altered cytokine production that leads to altered inflammatory responses and, hence, contributes to an otitis-prone condition.
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http://dx.doi.org/10.1542/peds.2007-0524DOI Listing
October 2007

The 4G/4G plasminogen activator inhibitor-1 genotype is associated with frequent recurrence of acute otitis media.

Pediatrics 2007 Aug;120(2):e317-23

Department of Pediatrics, Erasmus MC-Sophia Rotterdam, Dr Molewaterplein 50, Room Ee15-02, 3015 GE Rotterdam, The Netherlands.

Objectives: Plasminogen activator inhibitor-1 counterregulates cell migration, adhesion, and tissue repair. The PAI1 4G/5G promoter polymorphism has an effect on expression levels of PAI1. After a first acute otitis media episode, children are at increased risk for a next episode. Because the PAI1 4G allele is associated with higher plasminogen activator inhibitor-1 production and, hence, decreased tissue repair, we hypothesize that this allele may contribute to increased recurrence of acute otitis media.

Patients And Methods: The PAI1 4G/5G polymorphism was genotyped in 348 Dutch children aged 1 to 7 years who were suffering from recurrent acute otitis media and participating in a randomized, controlled trial and 463 healthy control subjects, representative of the general population.

Results: No significant difference in PAI1 genotype distribution between the whole acute otitis media group and control subjects was observed. However, children with the PAI1 4G/4G genotype had an increased risk of more frequent acute otitis media episodes compared with those who were homozygous for the 5G variant, also after correction for cofactors. This finding was attributable to children <4 years of age.

Conclusions: Our findings suggest that the PAI1 4G/4G genotype is associated with an increased risk for the otitis-prone condition, potentially because of impaired healing after a previous otitis media episode.
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http://dx.doi.org/10.1542/peds.2006-1390DOI Listing
August 2007

Toll-like receptor 2 polymorphism is associated with preterm birth.

Pediatr Res 2007 Oct;62(4):474-6

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 AB, The Netherlands.

Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p < 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth.
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http://dx.doi.org/10.1203/PDR.0b013e31813c9401DOI Listing
October 2007

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

Vaccine 2007 Jan 2;25(2):306-13. Epub 2006 Aug 2.

Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.vaccine.2006.07.024DOI Listing
January 2007

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

J Allergy Clin Immunol 2006 Jun 27;117(6):1344-50. Epub 2006 Apr 27.

Department of Pediatric Immunology, University Medical Center Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.jaci.2006.01.031DOI Listing
June 2006

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

Pediatrics 2006 Mar;117(3):603-8

Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands.

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.
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http://dx.doi.org/10.1542/peds.2005-0940DOI Listing
March 2006

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

Vaccine 2006 Feb 22;24(6):792-7. Epub 2005 Aug 22.

Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, KC03.063.0, 3584 EA Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.vaccine.2005.08.029DOI Listing
February 2006

Immunologic screening of children with recurrent otitis media.

Curr Allergy Asthma Rep 2005 Jul;5(4):302-7

Department of Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, KC03.063.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1007/s11882-005-0070-4DOI Listing
July 2005

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

J Clin Immunol 2005 Jan;25(1):78-86

Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1007/s10875-005-0361-8DOI Listing
January 2005