Hygiene hypothesis and innate immunity. evaluating the role of environmental factors and genetic polymorphisms on the expression of receptors of the innate immune system

Background In ‘westernised’ countries, the prevalence of childhood asthma and allergy has risen throughout the last few decades. A series of epidemiological studies showed reduced prevalence of asthma and allergy among farmers’ children compared to non-farmers’ children. These findings were in favour of the so-called ‘hygiene hypothesis’: Limited exposure to bacterial and viral pathogens during early childhood results in a higher risk of developing allergic diseases. Pattern-recognition receptors (PRR) of the innate immune system, such as toll-like receptors (TLR) or CD14, recognize microbial compounds. Activation of PRR signalling pathways initiates regulatory mechanisms which might be the biological basis for the protective effect of the farming environment. Gene-environment interactions have been found for several genetic polymorphisms in PRR genes, therefore differing environmental exposures between study populations might explain the conflicting results of genetic studies. Objectives To assess factors of the farming environment that influence the innate immune system with respect to gene expression of crucial proteins of innate immunity pathways and test if this association is modulated by unknown genetic factors. Methods The PARSIFAL study was a multi-center cross-sectional survey in rural areas across Europe. 14893 children aged 5-13 years (farmer’s children, children attending Steiner schools, and their respective control groups) completed a standardised questionnaire. Specific IgE to common inhalant and food allergens were obtained from selected children. Indoor dust samples were collected. Furthermore, gene expression measurements and SNPs (single nucleotide polymorphisms) of PRR were available. Results Gene expression of CD14, TLR2, and TLR4 was higher in farmers’ children compared to non-farmers’ children. Mainly prenatal factors accounted for these differences. Expression of PRR was higher in children when the mother worked on the farm during pregnancy. In addition, we observed a dose-dependent increase in gene expression of CD14, TLR2 and TLR4 with the number of farm animal species the mother had contact with during pregnancy, which probably serves as proxy for an increasing variation in microbial exposure. Prenatal factors also exert their effect on the child’s health later in life. Children of mothers who worked on the farm during pregnancy were less sensitised at school age to common inhalant and food allergens than children of unexposed mothers. However, the development of clinical symptoms of atopic diseases seemed to depend on exposures that occurred postnatally. Farm milk consumption was significantly associated with lower prevalence of atopic sensitisation and atopic health outcomes. Of particular importance is the consistency of the findings across the four study groups. Neither of the genotyped SNPs of innate immunity genes was directly associated with differential gene expression. However, a polymorphism in the CD14 gene (CD14/A-1721G) significantly modified the effect of farm milk consumption on CD14 gene expression. Farm milk drinking children homozygous for the A allele expressed significantly more CD14 than non-exposed children. No association between farm milk drinking was observed in children with the GG genotype, heterozygous children showed an intermediate difference in CD14 gene expression between exposed and non-exposed children. We observed the same interaction between genotypes of CD14/A-1721G and farm milk exposure on asthma and related atopic health outcomes. Moreover, we were able to replicate the gene-environment interaction on atopic health outcomes in two independent populations. Conclusions and Outlook Whereas the manifestation of atopic diseases such as asthma and allergies depends on postnatal exposures, protection against atopic sensitisation is conferred by prenatal exposure to a farming environment. Immune modulation by activation of innate immune mechanisms might underlay these observations. However, these results need confirmation by longitudinal studies. Despite limited power we could show a interaction between farm milk consumption and a CD14 polymorphism. Genome wide association studies study might give further insight into the interplay between genetics, environment and atopic diseases. Current scientific evidence has not developed strongly enough to provide a reliable course of action for primary prevention or therapy. Infectious diseases resulting from exposure to pathogens continue to be a serious public health problem. However, further investigation and characterisation of environmental compounds conferring protection against atopic diseases is promising and will hopefully result in future efficient preventive measures

Induction of Specific Immunotherapy with Hymenoptera Venoms Using Ultrarush Regimen in Children: Safety and Tolerance

Background & Objective. Ultrarush induction for specific venom immunotherapy has been shown to be reliable and efficacious in adults. In this study its safety and tolerance in children was evaluated. Methods. Retrospective analysis of 102 ultrarush desensitizations carried out between 1997 and 2005 in 94 children, aged 4 to 15 years. Diagnosis and selection for immunotherapy were according to recommendations of the European Academy of Allergy and Clinical Immunology. Systemic adverse reactions (SARs) were described using the classification of H. L. Mueller. Results. All patients reached the cumulative dose of 111.1 μg hymenoptera venom within 210 minutes. Six patients (6%) had allergic reactions grade I; 2 patients (2%) grade II and 5 patients (5%) grade III. Three patients (3%) showed unclassified reactions. SARs did not occur in the 15 patients aged 4 to 8 years and they were significantly more frequent in girls (29%) compared with boys (12%) (P = 0.034, multivariant analysis) and in bee venom extract treated patients (20%) compared to those treated with wasp venom extract (8%) (OR 0.33, 95% Cl 0.07–1.25). Conclusion. Initiation of specific immunotherapy by ultrarush regimen is safe and well tolerated in children and should be considered for treating children with allergy to hymenoptera venom

Respiratory muscle training improves respiratory muscle endurance but not exercise tolerance in children with cystic fibrosis

BACKGROUND: Respiratory muscle endurance (RME) training has been shown to increase exercise endurance and lung function in adults with cystic fibrosis (CF). We conducted an interventional study to investigate the effectiveness of RME training on CF-related health outcomes in children. METHODS: In a crossover trial, 22 children, aged 9-18 years, with CF performed 8 weeks of RME training and standard chest physiotherapy in a randomized sequence separated by a 1 week washout period. All children underwent training sessions using the RME training device before beginning the study. The primary outcomes were RME (in minutes) and exercise endurance (in minutes). Data were analyzed according to the intention-to-treat principle. RESULTS: Sixteen of 22 children (73%) completed the study. Study dropouts tended to be older with more advanced lung disease. After RME training, respiratory muscle endurance significantly increased by 7.03 ± 8.15 min (mean ± standard deviation, P < 0.001), whereas exercise endurance was unchanged by RME training (0.80 ± 2.58 min, P = 0.169). No significant improvement in secondary outcomes (lung function, CF quality of life, and CF clinical score) were observed. The small sample size and short intervention time have to be acknowledged as limitations of our study. CONCLUSIONS: RME training led to a significant increase in respiratory muscle endurance in children with CF. However, RME training did not improve exercise endurance or other CF-related health outcomes. Thus, our results do not support the routine use of RME training in the care of children with CF. Future studies in larger populations and with prolonged intervention time may overcome the limitations of our stud

Blood plasma lipidome profile of dairy cows during the transition period

BACKGROUND: The transition period of dairy cows, around parturition and the onset of lactation, involves endocrine and metabolic changes to compensate for an increased energy requirement aggravated by reduced feed intake. Transition cows adjust to the resulting negative energy balance with the mobilization of lipids from the adipose tissues yielding increased blood levels of non-esterified fatty acids and ketone bodies like β-hydroxybutyrate. RESULTS: To study the biochemical adaptations underlying this physiologic adjustment and possible pathologic derangements, we analyzed the blood plasma lipidome of transition cows by ultra-pressure liquid chromatography coupled to high-resolution quadrupole time-of-flight mass spectrometry. The resulting data were processed by principal component analysis, revealing over 60 lipid masses that change in abundance over the test period ranging from two weeks before calving to four weeks postpartum. Further characterization of analytes by tandem mass spectrometry demonstrated that the concentration of triacylglycerides in plasma drops at the day of parturition whereas the plasma level of many phosphatidylcholines and two sphingomyelins increases steadily during early lactation. CONCLUSION: This newly identified shift in phospholipid composition delivers a potential biomarker to detect aberrant metabolic pathways in transition cows and also provides insights into how to prevent and treat associated disorders like fatty liver disease

Perspective on cystic fibrosis and physical activity: Is there a difference compared to healthy individuals?

OBJECTIVES: The aim of this study was to compare habitual physical activity between cystic fibrosis (CF) patients and healthy controls and to investigate possible predictors for reduced physical activity in CF patients. METHODS: Sixty-six patients with CF (3-44 years) and 65 healthy controls (3-55 years) were asked to wear an accelerometer (Actigraph GT1M) for 9 days (at least 10 hr/day). Physical activity was classified in five categories from very low to very strenuous. RESULTS: In general, there was no difference in physical activity between CF patients and healthy controls. However, young school-aged 6-13 years old children with CF spent less time with strenuous and very strenuous activity than healthy controls (adjusted difference in activity -0.43 (-0.69, -0.17)). Patients with very low lung function were significantly less active, but other CF-associated conditions did not affect physical activity. CONCLUSIONS: While we found similar levels of physical activity measured by accelerometry in patients with CF compared to healthy controls in general, young school-aged children showed less engagement in strenuous activities than their healthy counterparts. As the reduced physical activity in young school children was not likely to be explained by the disease state, strenuous physical activity may be enhanced by advocating exercise and sport. Pediatr Pulmonol. 2016;51:1020-1030. © 2016 Wiley Periodicals, Inc

Expression of genes related to anti-inflammatory pathways are modified among farmers' children

The hygiene hypothesis states that children exposed to higher loads of microbes such as farmers' children suffer less from allergies later in life. Several immunological mechanisms underpinning the hygiene hypothesis have been proposed such as a shift in T helper cell balance, T regulatory cell activity, or immune regulatory mechanisms induced by the innate immunity.; To investigate whether the proposed immunological mechanisms for the hygiene hypotheses are found in farmers' children.; We assessed gene expression levels of 64 essential markers of the innate and adaptive immunity by quantitative real-time PCR in white blood cells in 316 Swiss children of the PARSIFAL study to compare farmers' to non-farmers' expressions and to associate them to the prevalence of asthma and rhinoconjunctivitis, total and allergen-specific IgE in serum, and expression of Cε germ-line transcripts.; We found enhanced expression of genes of the innate immunity such as IRAK-4 and RIPK1 and enhanced expression of regulatory molecules such as IL-10, TGF-β, SOCS4, and IRAK-2 in farmers' children. Furthermore, farmers' children expressed less of the TH1 associated cytokine IFN-γ while TH2 associated transcription factor GATA3 was enhanced. No significant associations between the assessed immunological markers and allergic diseases or sensitization to allergens were observed.; Farmers' children express multiple increased innate immune response and immune regulatory molecules, which may contribute to the mechanisms of action of the hygiene hypothesis

Pulmonary Function Test Abnormalities in Pediatric Inflammatory Bowel Disease

BACKGROUND Pulmonary involvement in adult patients with inflammatory bowel disease (IBD) seems more common than previously appreciated. Its prevalence and development over time in pediatric IBD patients are largely unknown. OBJECTIVES The aim was to study lung function including fraction of exhaled nitric oxide (FeNO) and transfer capacity for carbon monoxide (TLCO) in pediatric IBD patients and to describe the longitudinal development in a subset of patients with lung function abnormalities. METHODS Sixty-six measurements were made in 48 IBD patients (30 patients with Crohn's disease and 18 with ulcerative colitis) and 108 matched controls. Patients with abnormal TLCO or elevated residual volume/total lung capacity (RV/TLC) ratios were invited for a follow-up. Statistical comparisons were made by nonparametric tests and ANOVA. RESULTS TLCO was decreased in IBD patients [median: 88% predicted (interquartile range, IQR, 22) vs. 99% predicted (IQR 19) in controls]. RV/TLC ratios were mildly elevated in patients with ulcerative colitis [32% (IQR 9) vs. 27% (IQR 8) in controls], and maximum expiratory flows at 50 and 25% of vital capacity were mildly reduced in patients with Crohn's disease. FeNO and disease activity did not correlate with lung function abnormalities. Abnormalities did not consistently persist over a median follow-up period of 34 months. CONCLUSIONS This study supports evidence that variable and fluctuating pulmonary involvement also occurs in pediatric IBD patients. Its clinical significance is unclear. © 2015 S. Karger AG, Basel

Exposure to nonmicrobial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis

BACKGROUND Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases, such as allergy, asthma, and inflammatory bowel disease. OBJECTIVE We sought to investigate whether both exposure to microbes and exposure to structures of nonmicrobial origin, such as the sialic acid N-glycolylneuraminic acid (Neu5Gc), might play a significant role. METHODS Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in sera of children enrolled in 2 farm studies: the Prevention of Allergy Risk factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 299) and the Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort (cord blood [n = 836], 1 year [n = 734], 4.5 years [n = 700], and 6 years [n = 728]), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models, and the role of Neu5Gc in regulating immune activation was assessed based on helper T-cell and regulatory T-cell activation in mice. RESULTS In children anti-Neu5Gc IgG levels correlated positively with living on a farm and increased peripheral blood forkhead box protein 3 expression and correlated inversely with wheezing and asthma in nonatopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17+ T-cell numbers and supported differentiation of regulatory T cells. CONCLUSIONS In addition to microbial exposure, increased exposure to non-microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment

Aortopexy for the treatment of tracheobronchomalacia in 100 children: a 10-year single-centre experience

OBJECTIVES Our study describes and analyses the results from aortopexy for the treatment of airway malacia in children. METHODS Demographic data, characteristics and preoperative, operative and outcome details, including the need for reintervention, were collected for children undergoing aortopexy between 2006 and 2016. RESULTS One hundred patients [median age 8.2 months, interquartile range (IQR) 3.3-26.0 months] underwent aortopexy. Sixty-four (64%) patients had tracheomalacia (TM) only, 24 (24%) patients had TM extending into their bronchus (tracheobronchomalacia) and 11 (11%) patients had bronchomalacia. Forty-one (41%) children had gastro-oesophageal reflux disease, of which 17 (41%) children underwent a Nissen fundoplication. Twenty-eight (28%) children underwent a tracheo-oesophageal fistula repair prior to aortopexy (median 5.7 months, IQR 2.9-17.6 months). The median duration of follow-up was 5.3 years (IQR 2.9-7.5 years). Thirty-five (35%) patients were on mechanical ventilatory support before aortopexy. Twenty-seven (77%) patients could be safely weaned from ventilator support during the same admission after aortopexy (median 2 days, IQR 0-3 days). Fourteen patients required reintervention. Overall mortality was 16%. Multivariable analysis revealed preoperative ventilation (P = 0.004) and bronchial involvement (P = 0.004) to be adverse predictors of survival. Only bronchial involvement was a predictor for reintervention (P = 0.012). CONCLUSIONS Aortopexy appears to be an effective procedure in the treatment of children with severe airway malacia. Bronchial involvement is associated with adverse outcome, and other procedures could be more suitable. For the treatment of severe airway malacia with isolated airway compression, we currently recommend aortopexy to be considered