Preventive allergen immunotherapy with inhalant allergens in children.

The efficacy and safety of preventive allergen immunotherapy (pAIT) in children are currently under investigation. Here, we provide an overview of pAIT with respiratory allergens concerning the prevention of new sensitizations, allergic disease onset and progression as well as further immunomodulatory effects. Three databases were searched for clinical pAIT studies in children. Selected publications were reviewed for preventive outcomes according to prevention level (primary, secondary, and tertiary), allergen type, administration route, dose, and treatment duration. The primary prevention approach appears safe but showed no allergen-specific effect on new sensitizations. Secondary prevention seems feasible and may induce regulatory T cell-mediated immunotolerance. The number of studies at these prevention levels is limited. Tertiary prevention with grass and/or tree pollen-based pAIT has shown efficacy in preventing disease progression from allergic rhinitis/conjunctivitis to asthma. Data on tertiary pAIT with house dust mites and other allergen types are inconclusive. Subcutaneous and sublingual routes appear similarly effective, but head-to-head comparative paediatric studies are scarce. Additionally, there are fewer placebo-controlled studies. Nevertheless, immunomodulatory outcomes of pAIT are encouraging. Currently, limited but favourably suggestive evidence is available for preventing respiratory allergic diseases in children by pAIT. Primary and secondary prevention have potential and warrant further investigation through well-designed studies.

Preventive sublingual immunotherapy with House Dust Mite extract modulates epitope diversity in pre-school children.

BACKGROUND: The preventive effect of allergen immunotherapy (AIT) on allergy and asthma development is currently assessed using primary and secondary AIT approaches. Knowledge of the immunological effects of these interventions is limited and the impact on epitope diversity remains to be defined. METHODS: We used high-density peptide arrays that included all known Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f) allergens and the whole proteome of Der f to study changes in House Dust Mite (HDM) linear peptide recognition during a 2-year preventive double-blind placebo-controlled sublingual HDM AIT pilot study in 2-5-year-old children with sensitization to HDM but without symptoms. RESULTS: Preventive AIT-treated patients showed significantly higher IgG epitope diversity to HDM allergens compared to placebo-treated individuals at 24 months of treatment (P < 0.05), while no increase in IgE diversity was seen. At 24 months of treatment, IgG4 diversity for HDM allergens was significantly higher in the pAIT-treated patients compared to placebo group (P < 0.05). Potentially beneficial changes in epitope recognition throughout the treatment are also seen in peptides derived from Der f proteome. CONCLUSION: These data suggest a beneficial immunomodulation of preventive sublingual immunotherapy at a molecular level by favoring a broader blocking repertoire and inhibiting epitope spreading.

Forceps versus snare polypectomies in colorectal cancer screening: are we adhering to the guidelines?

BACKGROUND AND STUDY AIMS: European guidelines for quality assurance in colorectal cancer screening recommend snare resection for polyps > 5 mm. The aim of this study was to investigate polypectomy technique according to lesion size and shape, and to assess adherence of endoscopists enrolled in the national quality assurance program to the European guidelines. PATIENTS AND METHODS: This cohort study included screening colonoscopies performed between 2007 and 2013 within a quality assurance program in Austria. Resection technique was analyzed according to lesion characteristics and endoscopy facility (private practices, hospitals, outpatient clinics) before publication of the EU guidelines (2007 - 2010) and adherence to the guidelines after publication (2011 - 2013). All surveillance colonoscopies and examinations with missing data were excluded. RESULTS: A total of 128 969 screening colonoscopies performed by 278 endoscopy units were included. The polyp detection rate was 39.6 % (n = 47 797) and 95.6 % of polyps were resected. Of polyps ≥ 5 mm, 46.0 % were resected using forceps and were therefore not treated in accordance with the guidelines. Forceps polypectomy of lesions 5 - 10 mm and > 10 mm decreased significantly in hospitals after implementation of the guidelines (both P < 0.0001). In private practices, there was no difference in forceps usage for polyps of 5 - 10 mm (P = 0.41) before and after the guidelines, and for polyps > 10 mm forceps usage even increased (P < 0.0001). Endoscopists' forceps removal rates for polyps ≥ 5 mm correlated significantly with respective adenoma detection rates (P = 0.0007, r p  - 0.187) and cecal intubation rates (P = 0.0001, r p  - 0.303). Among endoscopists in private practices, internists had slightly lower forceps removal rates for polyps ≥ 5 mm than surgeons, both before (47.2 % vs. 50.7 %; P = 0.014) and after publication of the guidelines (51.9 % vs. 53.5 %; P = 0.161). CONCLUSIONS: This study confirmed the importance of the European guidelines. The inclusion of adequate resection technique as a quality indicator in colorectal cancer screening programs is recommended.

The Induction of IL-33 in the Sinus Epithelium and Its Influence on T-Helper Cell Responses.

BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by epithelial activation and chronic T-cell infiltration in sinonasal mucosa and nasal polyps. IL-33 is a new cytokine of the IL-1 cytokine family that has a pro-inflammatory and Th2 type cytokine induction property. The role of IL-33 in the pathomechanisms of CRS and its interaction with other T cell subsets remain to be fully understood. METHODS: The main trigger for IL-33 mRNA expression in primary human sinonasal epithelial cells was determined in multiple cytokine and T-cell stimulated cultures. The effects of IL-33 on naïve, Th0 and memory T-cells was studied by PCR, ELISA and flow cytometry. Biopsies from sinus tissue were analyzed by PCR and immunofluorescence for the presence of different cytokines and receptors with a special focus on IL-33. RESULTS: IL-33 was mainly induced by IFN-γ in primary sinonasal epithelial cells, and induced a typical CRSwNP Th2 favoring cytokine profile upon co-culture with T-helper cell subsets. IL-33 and its receptor ST2 were highly expressed in the inflamed epithelial tissue of CRS patients. While IL-33 was significantly up-regulated in the epithelium for CRSsNP, its receptor was higher expressed in sinus tissue from CRSwNP. CONCLUSIONS: The present study delineates the influence of IL-33 in upper airway epithelium and a potential role of IL-33 in chronic inflammation of CRSwNP by enhancing Th2 type cytokine production, which could both contribute to a further increase of an established Th2 profile in CRSwNP.

High quality of screening colonoscopy in Austria is not dependent on endoscopist specialty or setting.

BACKGROUND AND STUDY AIM: International studies have shown differences in the outcome of screening colonoscopies related to the endoscopist's specialty and setting of colonoscopy. The aim of this study was to investigate the impact of these two factors on quality parameters for screening colonoscopy in a quality-assured screening program. METHODS: Adenoma detection rate (ADR), cecal intubation rate (CIR), polypectomy rate, flat polyp detection rate, carcinoma detection rate, sedation rate, complication rates, and other parameters of 59 901 screening colonoscopies performed by 178 endoscopists were analyzed in relation to specialty (35 gastroenterologists: 10 066 colonoscopies [16.8 %]; 84 nongastroenterologists: 26 271 colonoscopies [43.9 %]; 59 surgeons: 23 564 [39.3 %]), and setting (hospital: 12 580 [21.6 %] colonoscopies; office: 45 781 [78.4 %] colonoscopies). RESULTS: The overall ADR was 20.5 % and the CIR was 95.6 %. The ADR did not show any statistical significance, either in relation to specialty or to setting. A significant difference in the CIR was found between hospital-based and office-based internists (98.5 % vs. 96.8 %, respectively; P  = 0.0005; odds ratio [OR] 2.2, 95 % confidence interval [CI] 1.4 - 3.4). Hospital-based internists had a significantly higher flat polyp detection rate (7.5 % vs. 4.1 %; P  = 0.02; OR 1.9, 95 %CI 1.1 - 3.2) and a significantly lower carcinoma detection rate (0.4 % vs. 0.6 %; P  = 0.03; OR 0.7, 95 %CI 0.5 - 1.0) compared with office-based internists. Complication rates were significantly lower among surgeons than among internists (0.1 % vs. 0.2 %; P  = 0.03; OR 0.5, 95 %CI 0.3 - 1.0). CONCLUSION: Endoscopists participating in the Austrian quality assurance program offered high quality screening colonoscopy regardless of their specialty and setting. The implementation of a standardized quality program is therefore a decisive factor in quality improvement of screening colonoscopy.

Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects.

BACKGROUND: Prevention of new IgE sensitizations has been described during allergen-specific immunotherapy. However, prospective data using a preventive approach in very young children who would benefit most are missing. We initiated a prospective pilot study investigating the safety, immunomodulatory, and sensitization-preventive effect of sublingual immunotherapy (SLIT) in mono/oligoclonally sensitized, clinically asymptomatic children 2-5 yr of age. METHODS: In this double-blinded, randomized, placebo-controlled pilot study, 31 mono-/oligosensitized children to house-dust mite or grass pollen were included. SLIT with the respective source (n = 15) or placebo (n = 16) was applied. After dose-up-phase therapy was continued for 2 yr. Parents recorded clinical events, vaccinations, and drug intake in a diary. Skin prick testing and specific IgE and IgG measurements were recorded at baseline, 12 and 24 months. At the same time, allergen-specific proliferation and IL10- and TGFß-dependent Treg function were measured. RESULTS: Preventive application of SLIT in young children was safe (no relevant side effects in 21,170 single applications). After 12 and 24 months of treatment, the rate of allergen-specific sensitization (specific IgE and SPT reactivity) was comparable in the treatment and the placebo group. However, verum-treated patients displayed a significant up-regulation of allergen-specific IgG (p < 0.05). Furthermore, IL10-dependent inhibition (p < 0.05) was observed in vitro in the treatment group but not in the placebo group. CONCLUSION: Preventive SLIT is safe in children 2-5 yr of age and induces regulatory mechanisms involving allergen-specific IgG and IL10. Based on this pilot study, large-scale trials will need to investigate the modulation of sensitization and clinically relevant allergy.

Sex is a stronger predictor of colorectal adenoma and advanced adenoma than fecal occult blood test.

Due to high costs and limited availability of screening colonoscopy, some screening programs require a positive fecal occult blood test (FOBT) before screening colonoscopy is remunerated. As male sex is a strong predictor of adenoma and advanced adenoma, we evaluated whether a positive FOBT or male sex is a stronger risk factor for adenoma and advanced adenoma. FOBT and screening colonoscopy results from 18.665 consecutive patients participating in a "national health check program" between 2009 and 2011 were included in this cohort study. Age-corrected adenoma detection rates (ADR), advanced adenoma detection rates (AADR) and carcinoma detection rates were calculated for men and women according to FOBT result separately. ADR and AADR in FOBT-positive men (34.6 and 11.8 %) and FOBT-negative men (29.1 and 7.6 %) were higher than ADR and AADR in FOBT-positive women (20 and 6.9 %) and in FOBT-negative women (17.6 and 4.4 %), (p = 0.0003). Men with negative FOBT were at higher risk of having an adenoma and advanced adenoma than women with positive FOBT (p < 0.0001). Odds ratios of a positive FOBT for ADR and AADR were 1.3 (1.1-1.5) (p = 0.0047) and 1.6 (1.2-2.1) (p < 0.0001), respectively. Odds ratios of male sex to predict ADR and AADR were significantly higher with 1.9 (1.8-2.1) and 1.8 (1.6-2), respectively (p < 0.001). Male sex is a stronger predictor for colorectal adenoma and advanced adenoma than positive FOBT. These results should be taken into account analyzing FOBT-based screening programs.

Sedation in screening colonoscopy: impact on quality indicators and complications.

OBJECTIVES: Quality indicators including cecal intubation rate (CIR) and adenoma detection rate (ADR) are established. Sex differences of quality indicators are observed, but the influence of sedation has not been investigated so far. The objective of this study is to assess the impact of sedation on quality indicators, including CIR and ADR, according to sex. METHODS: We analyzed data of 52,506 screening colonoscopies performed by 196 endoscopists between November 2007 and April 2011 according to the Austrian "quality management for colon cancer prevention" program. RESULTS: Sedation did not affect polyp detection rate (women P=0.7972, men P=0.3711) or ADR for both sexes (women P=0.2773, men P=0.8676). ADR was not significantly influenced by sedation (P=0.1272), but by age and sex (both P<0.0001), when the executing endoscopist was considered. Although women were more often sedated than men (90.70 vs. 81.83%; P<0.0001), CIR was slightly lower in women than in men (94.69 vs. 96.58%; P<0.0001). Sedation improved the CIR in women by 2.95% (94.96 vs. 92.01%; P<0.0001), whereas in men it was just by 1.28% (96.81 vs. 95.53%; P<0.0001). Sedated women only reached the CIR of unsedated men (94.96 vs. 95.53%; P=0.1005). Accounting for the intra-observer influence of the endoscopist, the overall CIR was influenced by the interaction of sex and age (P=0.0049), but not by sedation (P=0.1435). CONCLUSIONS: Sedation does not increase adenoma or polyp detection, although it leads to an increase in CIR in men and women. This effect is more pronounced in women, yet CIR of men remains higher compared with women. Quality indicators are mainly influenced by the patient's age, sex, and the endoscopists' individual performance, rather than the endoscopists' subspeciality or procedural experience.

Fc-epsilon-RI, the high affinity IgE-receptor, is robustly expressed in the upper gastrointestinal tract and modulated by mucosal inflammation.

BACKGROUND: The role of the high affinity IgE receptor, FcεRI, in IgE-mediated immune responses of the gastrointestinal (GI) mucosa is poorly understood. Currently, a detailed characterization of FcεRI expression throughout the human gut is lacking. The aim of this study was to define the expression pattern of FcεRI in the GI tract. METHODS/PRINCIPAL FINDINGS: We compared FcεRI expression in children with gastritis/esophagitis (n = 10), celiac disease (n = 10), inflammatory bowel disease (IBD) (n = 9), and normal mucosa (n = 5). The α-subunit of FcεRI (FcεRIα), detected by immunohistochemistry, was found on cells infiltrating the mucosa of the esophagus, the stomach, and the duodenum, but was rarely detected in more distal sections of the GI tract. Accordingly, quantitative RT-PCR analysis on esophagus, stomach, duodenum, colon, and rectum biopsies revealed that FcεRIα and -ß expression levels decreased towards the distal intestine. mRNA transcripts of the common Fc-receptor-γ chain were present in the entire GI mucosa. Double-immunofluorescence staining of esophageal specimens confirmed that FcεRIα was expressed on intraepithelial mast cells and Langerhans cells. The mRNA expression levels of the α, ß, and γ subunits of FcεRI did not correlate with total serum IgE but were associated with mucosal inflammation. CONCLUSION/SIGNIFICANCE: Our data define the upper GI tract as the main site for IgE-mediated immune activation via FcεRI. Tissue mRNA levels of FcεRIα are regulated by inflammatory conditions rather than serum IgE, indicating that FcεRI might also play a role in pathologies other than allergy.

Cord blood derived CD4+ CD25(high) T cells become functional regulatory T cells upon antigen encounter.

BACKGROUND: Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these "excessive" responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. METHODS: Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([(3)H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4(+)CD25(high)FoxP3(+) T cells were characterized by mRNA analysis and flow cytometry. RESULTS: Cord blood derived CD4(+)CD25(high) cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4(+)CD25(high) cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3(+)CD4(+)CD25(high)cells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4(+)CD25(+)CD127(low)) is highly suppressive even without prior antigen exposure. CONCLUSION: Cord blood harbors a very small subset of CD4(+)CD25(high) Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs.

Sex-specific prevalence of adenomas, advanced adenomas, and colorectal cancer in individuals undergoing screening colonoscopy.

CONTEXT: Although some studies have shown that men are at greater age-specific risk for advanced colorectal neoplasia than women, the age for referring patients to screening colonoscopy is independent of sex and usually recommended to be 50 years. OBJECTIVE: To determine and compare the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas (AAs), and colorectal carcinomas (CRCs) for different age groups in men and women. DESIGN, SETTING, AND PATIENTS: Cohort study of 44,350 participants in a national screening colonoscopy program over a 4-year period (2007 to 2010) in Austria. MAIN OUTCOME MEASURES: Prevalence and NNS of adenomas, AAs, and CRCs in different age groups for men and women. RESULTS: The median ages were 60.7 years (interquartile range [IQR], 54.5-67.5 years) for women and 60.6 years (IQR, 54.3-67.6 years) for men, and the sex ratio was nearly identical (51.0% [22,598] vs 49.0% [21,572]). Adenomas were found in 19.7% of individuals screened (95% CI, 19.3%-20.1%; n = 8743), AAs in 6.3% (95% CI, 6.1%-6.5%; n = 2781), and CRCs in 1.1% (95% CI, 1.0%-1.2%; n = 491); NNS were 5.1 (95% CI, 5.0-5.2), 15.9 (95% CI, 15.4-16.5), and 90.9 (95% CI, 83.3-100.0), respectively. Male sex was significantly associated with a higher prevalence of adenomas (24.9% [95% CI, 24.3%-25.4%] vs 14.8% [95% CI, 14.3%-15.2%]; P < .001; unadjusted odds ratio [OR], 1.9 [95% CI, 1.8-2.0]), AAs (8.0% [95% CI, 7.6%-8.3%] vs 4.7% [95% CI, 4.4%-4.9%]; P < .001; unadjusted OR, 1.8 [95% CI, 1.6-1.9]), and CRCs (1.5% [95% CI, 1.3%-1.7%] vs 0.7% [95% CI, 0.6%-0.9%]; P < .001; unadjusted OR, 2.1 [95% CI, 1.7-2.5]). The prevalence of AAs in 50- to 54-year-old individuals was 5.0% (95% CI, 4.4%-5.6%) in men but 2.9% (95% CI, 2.5%-3.4%) in women (adjusted P = .001); the NNS in men was 20 (95% CI, 17.8-22.6) vs 34 in women (95% CI, 29.1-40; adjusted P = .001). There was no statistical significance between the prevalence and NNS of AAs in men aged 45 to 49 years compared with women aged 55 to 59 years (3.8% [95% CI, 2.3%-6.1%] vs 3.9% [95% CI, 3.3%-4.5%] and 26.1 [95% CI, 16.5-44.4] vs 26 [95% CI, 22.5-30.2]; P = .99). CONCLUSION: Among a cohort of Austrian individuals undergoing screening colonoscopy, the prevalence and NNS of AAs were comparable between men aged 45 to 49 years and women aged 55 to 59 years.