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Background: Toll-interacting protein is a key factor in regulating innate immunity responses via gatekeeping Toll-like receptors. Genetic variance in innate immunity has been linked with susceptibility to infections. Children with viral bronchiolitis in infancy are at increased risk of later asthma. The aim was to evaluate the role of toll-interacting protein gene point mutations in severity of bronchiolitis and subsequent risk of asthma. Methods: Infants less than 6 months old were recruited during hospitalization due to bronchiolitis. In all, 166 children were prospectively followed up to age of 1.5, 6, and 11 years. Clinical data on viral etiology and severity markers, and further post-bronchiolitis asthma and lung function outcomes were compared with genetic differences in two single-nucleotide point mutations rs116938768 and rs5743854 in the toll-interacting protein gene. Results: Toll-interacting protein rs116938768 or rs5743854 did not show significant associations with severity markers or viral etiology of bronchiolitis. Follow-up data on current asthma or lung function at 6 or 11 years of age after bronchiolitis were not associated with the investigated mutations. Conclusion: Toll-interacting protein gene point mutations in rs116938768 or rs5743854 were not involved with the clinical course of viral bronchiolitis in early infancy, and did not predict post-bronchiolitis asthma or lung function reduction by the age of 11 years. publishedVersion

Background Interleukin-17A (IL-17A) and IL-17F are involved in the pathogenesis of asthma and allergy. Interleukin-17 receptor A (IL-17RA), encoded by the IL17RA gene, is a common receptor for IL-17A and IL-17F. The aim of the present study was to evaluate the association of IL17RA gene variations with asthma, allergy, and lung function at school age in children prospectively followed up after hospitalization for bronchiolitis in early infancy. Methods Data on IL17RA rs4819553, rs4819554, and rs4819558 polymorphisms and clinical outcomes, including asthma and allergic rhinitis, were available for 145 former bronchiolitis patients at 5-7 years and for 125 at 11-13 years of age. One hundred children underwent impulse oscillometry at 5-7 years and 84 underwent flow-volume spirometry at 11-13 years of age. The IL17RA rs4819553, rs4819554 and rs4819558 were completely co-segregating in Finnish children in our previous studies. Results The distributions of the studied IL17RA wild versus variant genotypes and major versus minor allele frequencies did not differ between bronchiolitis cases and population controls. These variations showed no significant association with asthma or allergic rhinitis nor with lung function reduction at 5-7 or 11-13 years of ages. Only 5.6% to 6.4% of the variations were homozygous. Conclusions The IL17RA gene variations that were studied showed no association with susceptibility to severe bronchiolitis in infancy, nor with post-bronchiolitis asthma or lung function at school age. Future studies should evaluate other IL17RA polymorphisms and include more cases, and especially cases with homozygous variations.

Aim Evidence based on studies of the encoding genes suggests that interleukin-1 receptor-associated kinase-4 (IRAK4) plays a role in childhood asthma and allergy. Our aim was to evaluate the associations of six IRAK4 gene polymorphisms with presence of asthma and allergic rhinitis and use of inhaled corticosteroids (ICSs) for asthma at 5-7 and 11-13 years of ages after hospitalisation for bronchiolitis at younger than 6 months of age. Methods IRAK4 rs4251513, rs4251520, rs4251522, rs4251578, rs79154645 and rs13852554 polymorphisms were determined in 141 former bronchiolitis patients prospectively followed up until 5-7 and in 125 children until 11-13 years of age. Results The homozygous variant IRAK4 rs4251513 genotype was associated with the presence of asthma and allergic rhinitis and use of ICSs at 5-7 and 11-13 years of ages in univariate analyses. Statistical significance remained for the presence of asthma and use of ICSs but was lost in the case of allergic rhinitis in multivariate analyses. The adjusted odds ratios were 3.48 and 4.16 for asthma and 5.22 and 14.00 for ICS use at these two ages. Conclusion The homozygous variant IRAK4 rs4251513 genotype was constantly associated with post-bronchiolitis asthma and asthma medication in school-aged children.

Aim Interleukin-17F (IL-17F) is involved with asthma. The aim of this study was to evaluate the association of IL17F polymorphisms with childhood asthma after bronchiolitis in infancy. Methods We invited 166 children who were hospitalised for bronchiolitis at younger than 6 months of age to follow-up visits at 5-7 years and 11-13 years of ages. Asthma and allergy diagnoses, asthma-presumptive symptoms and use of inhaled corticosteroids (ICSs) were registered. Blood samples were available for IL17F rs763780 (T/C), rs11465553 (C/T) and rs7741835 (C/T) determinations in 165 cases. Results The presence of IL17F rs11465553 and rs7741835 variations showed no significant associations with any asthma or allergy outcome at either 5-7 years or 11-13 years of ages. Instead, children with the variant IL17F rs763780 genotype had used more often ICSs between the follow-up visits from 5-7 to 11-13 years (adjusted OR 3.58) than those with the wild genotype. Children with the variant IL17F rs763780 genotype reported more often doctor-diagnosed atopic dermatitis (adjusted OR 2.71) at 11-13 years of age than those with the wild genotype. Conclusion This prospective long-term follow-up study provided preliminary evidence on the association of the IL17F rs763780 polymorphism with asthma at school age after bronchiolitis in infancy.

Blood myxovirus resistance protein A (MxA) has broad antiviral activity, and it is a potential biomarker for symptomatic virus infections. Limited data is available of MxA in coinciding viral and bacterial infections. We investigated blood MxA levels in children hospitalized with a febrile urinary tract infection (UTI) with or without simultaneous respiratory virus infection. We conducted a prospective observational study of 43 children hospitalized with febrile UTI. Nasopharyngeal swab samples were collected at admission and tested for 16 respiratory viruses by nucleic acid detection methods. Respiratory symptoms were recorded, and blood MxA levels were determined. The median age of study children was 4 months (interquartile range, 2–14 months). A respiratory virus was detected in 17 (40%) children with febrile UTI. Of the virus-positive children with febrile UTI, 7 (41%) had simultaneous respiratory symptoms. Blood MxA levels were higher in virus-positive children with respiratory symptoms (median, 778 [interquartile range, 535–2538] μg/L) compared to either virus-negative (155 [94–301] μg/L, P P = 0.006) children without respiratory symptoms at presentation with febrile UTI. MxA differentiated virus-positive children with respiratory symptoms from virus-negative without symptoms by an area under the receiver operating characteristic curve of 0.96. Respiratory viruses were frequently detected in children with febrile UTI. In UTI with simultaneous respiratory symptoms, host antiviral immune response was demonstrated by elevated blood MxA protein levels. MxA protein could be a robust biomarker of symptomatic viral infection in children with febrile UTI.

AIM Interleukin (IL)-33, encoded by the IL33 gene, is associated with allergy and asthma. We evaluated IL33 rs1342326 polymorphism in relation to asthma, asthma medication and allergic rhinitis after infant bronchiolitis. METHODS IL33 rs1342326 polymorphism was studied in children, who were hospitalised for bronchiolitis at age younger than 6 months and who were prospectively followed until 5-7 years (N = 141) and 11-13 years (N = 125) of ages. RESULTS The presence of the wild AA vs variant AC or CC genotypes of the IL33 rs1342326 showed no significant associations with previous or current asthma at the mean ages of 6.4 or 11.7 years. However, 22.5% of children with the variant genotype used inhaled corticosteroids at the 5-7 years of visit (adjusted OR: 2.94, 95% CI: 1.04-8.33 vs those 8.9% with the wild genotype). The variant IL33 rs1342326 genotype was associated with allergic rhinitis at 6.4 years (adjusted OR: 2.17, 95% CI: 1.01-4.76) and 11.7 years (3.23, 1.18-9.09) of ages. CONCLUSION The frequent use of asthma control medication in 6.4-year-old children with IL33 rs1342326 polymorphism suggests that this variation may increase susceptibility to severe asthma at preschool age. The IL33 rs1342326 variant genotype was associated with a 3-fold risk of allergic rhinitis at school age.

AIM The aim of the study was to evaluate the association of Toll-like receptor 4 (TLR4) gene variations with osteitis risk after Bacillus Calmette-Guerin (BCG) vaccination given at birth and with serum cytokine levels measured in adulthood. METHODS We determined the TLR4 rs4986790 single-nucleotide polymorphism (SNP) in 132 study subjects with BCG osteitis in infancy and compared the genotype distributions and allele frequencies between them and population controls. Serum concentrations of 11 cytokines measured in adulthood were compared between study subjects with the wild vs variant TLR4 rs4986790 genotype. RESULTS The genotypes and allele frequencies of the TLR4 rs4986790 SNP did not differ between BCG osteitis cases and population controls. Instead, subjects with the variant genotype presented with lower serum interleukin (IL) concentrations of the pro-inflammatory IL-6, IL-17A and IL-12 cytokines and with marginally lower interferon-γ concentrations, but with higher serum anti-inflammatory IL-4 concentration. The results concern also the TLR4 rs4986791, since these two SNPs are co-segregating in the Finnish population. CONCLUSION The findings suggest that TLR4 has no significant role in the emergence of osteitis after newborn BCG vaccination, but the variant genotypes of the TLR4 rs4986790 and rs4986791 may impair the production of pro-inflammatory cytokines.

Interleukin-33 (IL-33), a cytokine of the IL-1 family, has both pro-inflammatory and anti-inflammatory properties and shares a common receptor with IL-1. Single nucleotide polymorphism (SNP) at rs1342326 of the IL33 gene was associated with allergic rhinitis in preschool-aged children from five European countries (1), and has been associated with wheezing, asthma and hospitalisation for asthma in other child populations (2).

Interleukin (IL) 1 receptor-like 1, encoded by the IL1RL1 gene, is a receptor for IL-33. In European birth cohorts, IL1RL1 rs102082293, rs10204137 (rs4988955), rs13424006 and rs13431828 (rs13048661) variations were associated with asthma at school age. In a Dutch multi-centre study, IL1RL1 rs1921622 variation was associated with severe bronchiolitis. We evaluated the associations of these five IL1RL1 variations with asthma and lung function at school age after hospitalisation for bronchiolitis in infancy.Follow-up data, including impulse oscillometry at age 5-7 and flow-volume spirometry at age 11-13 years, and the IL1RL1 genotype data were available for 141 children followed until 5-7 and for 125 children followed until 11-13 age years after bronchiolitis in infancy. The IL1RL1 rs10204137 and rs4988955, and the IL1RL1 rs13048661 and rs13431828, are 100% co-segregating in the Finnish population.The variant IL1RL1 rs13048661/13431828 genotype was constantly associated with increased asthma risk by various definitions at 5-7 and 11-13 years of ages. The result was confirmed with analyses adjusted for current confounders and early-life environment-related factors. Statistical significances were lost, when maternal asthma and atopic dermatitis in infancy were included in the model.IL1RL1 rs13048661/13431828 variation was associated with post-bronchiolitis asthma outcomes at school age.

Interleukin-1 receptor associated kinase-4 (IRAK4) encoded by the IRAK4 gene mediates signals of innate immunity. Single nucleotide polymorphisms (SNP) of the IRAK4 rs4251513 and rs4251520 were associated with an increased risk of early transient wheezing, when 94 SNPs were studied in 2007 Dutch and 7242 French children prospectively followed-up for eight years from birth (1).

AIM Toll-like receptor 1 (TLR1), TLR2, TLR6 and TLR10 form the TLR2 subfamily. In our previous controlled studies in 132 subjects with osteitis after newborn Bacillus Calmette-Guerin (BCG) vaccination, TLR1, TLR2 and TLR6 variations were associated with the risk of BCG osteitis. Now, we evaluated the role of ten single nucleotide polymorphisms (SNP) of the TLR10 gene in this cohort. METHODS Five synonymous TLR10 SNPs (rs10004195, rs10856837, rs10856838, rs1109695 and rs11466652), and five missense TLR10 SNPs (rs11096955, rs11096957, rs11466649, rs11466653 and rs11466658) were determined by polymerase chain reaction (PCR)-based sequencing in 132 former BCG osteitis patients. RESULTS TLR10 rs10004195 polymorphism was associated with the risk of BCG osteitis, compared to Finnish population controls. The variant genotype (AT/AA) was present in 13.6% of cases versus 26.2% of controls (p = 0.024). Correspondingly, the minor allele frequency (MAF) was lower (0.075) in cases than in controls (0.152; p = 0.009). There were no significant differences in the genotypes of the other nine studied TLR10 SNPs or in the corresponding MAFs between cases and controls. CONCLUSION Among ten studied TLR10 gene polymorphisms, the variation only in the TLR10 rs10004195 was associated with the BCG osteitis risk after newborn BCG vaccination.

Aim Interleukin-17 (IL-17) family cytokines promote the host defence against mycobacterial infections. We have previously shown an association between IL17A variations and Bacillus Calmette-Guerin (BCG) osteitis. This paper evaluates the association of three IL17F polymorphisms with BCG osteitis after newborn vaccination. Methods IL17F rs763780, rs11465553 and rs7741835 single nucleotide polymorphisms (SNPs) were studied in 132 adults, who presented with BCG osteitis in infancy. The genotypes and minor allele frequencies (MAFs) were compared between cases and Finnish population-based controls (N = 99) from the 1000 Genomes Project, and MAFs were compared between cases and allele data of Finnish subjects from the large Genome Aggregation Database. Results There were no significant differences between former BCG osteitis patients and population-based controls in the IL17F rs763780 (wild 84.4% vs 84.8%), rs11465553 (86.4% vs 91.9%) or rs7741835 (65.7% vs 67.7%) genotypes. Homozygous variant genotypes were only present in 1.5%, 0.8% and 3.8% of cases, respectively. Likewise, MAFs of the three IL17F SNPs did not substantially differ from those of 11 252, 11 939 and 1371 Finnish subjects, respectively, from the available Genome Aggregation Database. Conclusion IL17F rs763780, rs11465553 and rs7741835 variations showed no association with the risk of BCG osteitis after newborn vaccination.

Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p

Background The transition from early childhood wheezing to persistent asthma is linked to lung function impairment over time. Little is known how the methods used to study lung function at different ages correlate longitudinally. Methods Sixty-four children with a history of hospitalization for bronchiolitis before 6 months of age were prospectively studied with impulse oscillometry (IOS) at the mean age of 6.3 years and these preschool IOS results were compared with flow-volume spirometry (FVS) measurements at mean age of 11.4 years. Results The baseline respiratory system resistance at 5 Hz (Rrs5) showed a modest statistically significant correlation with all baseline FVS parameters except FVC. The post-bronchodilator (post-BD) Rrs5 showed a modest statistically significant correlation with post-BD FEV1 and FEV1 /FVC. The bronchodilator-induced decrease in Rrs5 showed a modest statistically significant correlation with the percent increase in FEV1 . Baseline and post-BD respiratory reactance at 5 Hz (Xrs5) showed a modest statistically significant correlation with baseline and post-BD FVS parameters except post-BD FEV1 /FVC, respectively, and post-BD Xrs5 showed a strong correlation with post-BD FVC (ρ = 0.61) and post-BD FEV1 (ρ = 0.59). In adjusted linear regression, preschool Xrs5 remained as a statistically significant independent predictor of FVS parameters in adolescence; the one-unit decrease in the Z-score of preschool post-BD Xrs5 predicted 9.6% lower post-BD FEV1 , 9.3% lower post-BD FVC, and 9.7% lower post-BD MEF50 when expressed as %-predicted parameters. Conclusion Persistent post-BD small airway impairment in children with a history of bronchiolitis detected with IOS at preschool age predicted FVS results measured in early adolescence.

Toll-like receptors (TLR) are innate immunity molecules and our previous studies found that TLR1 gene polymorphism was associated with postbronchiolitis asthma at one to six years of age, as was TLR10 at five to seven years of age. This study examined any associations at 11-13 years of age.This prospective follow-up study was part of an ongoing evaluation of children admitted to Tampere University Hospital, Finland, for bronchiolitis in 2001-2004 at less than six months of age. We evaluated the association of TLR1 rs5743618 and TLR10 rs4129009 polymorphisms with asthma and asthma medication in 125 children aged 11-13 years.Associations were measured as adjusted odd ratios (aOR) with 95% confidence intervals (95% CI). The variant TLR1 rs5743618 (aOR 4.04, 95% CI 0.99-13.01) and TLR10 rs4129009 (aOR 7.02, 95% CI 1.56-31.53) genotypes increased the risk of needing inhaled corticosteroids (ICSs) at 11-13 years of age. The variant TLR10 genotype (aOR 7.69, 95% CI 1.35-43.95) increased the risk of persistent asthma continuing from five to seven years of age until 11-13 years of age. The results were similar when the combined genotypes were analysed. [Correction added on 3 October 2017, after online publication: The data in the variant TRL1 rs5743618 genotype were incorrect and have been corrected in this version.] CONCLUSION: Polymorphisms in both the TLR1 and TLR10 genes may increase the risk of asthma at 11-13 years after infant bronchiolitis.

Background Interleukin-17 (IL-17A) is a mainly pro-inflammatory cytokine, and IL-17 signaling implicates in the development of allergic asthma. The polymorphism rs2275913 in the promoter region of the IL-17A gene has in previous studies been associated with asthma susceptibility. The objective was to evaluate the association between IL-17A rs2275913 (-197G>A) polymorphism and post-bronchiolitis asthma and/or allergic rhinitis in a prospective 11–13 years post-bronchiolitis follow-up. Methods 166 previously healthy full-term infants, hospitalized for bronchiolitis at age less than 6 months, were invited to follow-up visits at the ages of 5–7 years and 11–13 years. Asthma diagnoses and presumptive symptoms, allergic rhinitis and use of inhaled corticosteroids (ICS) were registered. Blood samples for IL-17A rs2275913 (-197G>A) polymorphism were obtained during hospitalization or at the 5–7 years control visit. Results There were no significant differences between children with the wild GG and variant GA or AA genotype in the severity of bronchiolitis during hospitalization or in the outcomes until the age 5–7 years. At 11–13 years of age, children with the variant GA or AA genotype had significantly less often current asthma, use of ICSs during last 12 months or allergic rhinitis than those with the wild GG genotype. The ICS use during last 12 months retained the statistical significance in adjusted analyses (adjusted OR 0.25), whereas current asthma and allergic rhinitis marginally lost it. Conclusions The IL-17A rs2275913 (-197G>A) polymorphism decreased the risk of post-bronchiolitis asthma at 11–13 years of age, but not earlier in life, in the present prospective, long-term follow-up study.

Increasing evidence shows that environmental factors in childhood play a role in development of irreversible airway obstruction. We evaluated early-life and preschool-age risk factors for irreversible airway obstruction in adolescence after bronchiolitis in infancy.This study is a secondary analysis of data collected during prospective long-term follow-up of our post-bronchiolitis cohort. Risk factor data were collected during hospitalisation and on follow-up visits at 5-7 and 10-13 years of ages. Lung function was measured from 103 participants with impulse oscillometry at 5-7 years of age and from 89 participants with flow-volume spirometry at 10-13 years of age.Asthma diagnosis at12 months of age showed a significant association with irreversible airway obstruction at 10-13 years of age independently from current asthma. Irreversible airway obstruction was less frequent in children with variant than wild genotype of the Toll-like receptor 4(TLR4) rs4986790, but the significance was lost in logistic regression adjusted for current asthma and weight status. Higher post-bronchodilator respiratory system resistance at 5 Hz and lower baseline and post-bronchodilator reactance at 5 Hz by impulse oscillometry at 5-7 years of age were associated with irreversible airway obstruction at 10-13 years of age.Asthma diagnosis during the first living year and worse lung function at preschool age increased the risk for irreversible airway obstruction at 10-13 years of age after bronchiolitis. TLR4 rs4986790 polymorphism may be protective for development of irreversible airway obstruction after bronchiolitis.

Background Five studies carried out after bronchiolitis at less than 24 months of age, with a follow-up of more than 10 years, reported that atopic dermatitis, family asthma, early-life exposure to tobacco smoke and rhinovirus aetiology were early-life risk factors for later asthma. This study evaluated the long-term outcome at 11-13 years of age of children who were hospitalized for bronchiolitis in early infancy. Methods We previously prospectively followed 166 children hospitalized for bronchiolitis at less than 6 months of age until 5-7 years of age. The current study included a structured questionnaire, parental interviews, clinical examinations and bronchodilation test of 138 of those children at 11-13 years of age. Results Respiratory syncytial virus caused 66% of the bronchiolitis cases, and nearly half of the patients were exposed to tobacco smoke in early life. Doctor-diagnosed asthma was present in 13% of the former bronchiolitis patients at 11-13 years of age. Maternal asthma was the only independently significant risk factor in early life (adjusted OR 3.45, 95% CI 1.07-11.74), as was allergic rhinitis at 5-7 years of age (adjusted OR 4.06, 95% CI 1.35-12.25). Conclusions After bronchiolitis at less than 6 months of age, the risk of doctor-diagnosed asthma at 11-13 years was about twice that of the general Finnish population. Maternal asthma was the only independently significant early-life risk factor for current asthma at 11-13 years of age.

Aim Interleukin-17 (IL-17) appears to promote the host's defence against mycobacterial infections. This study evaluated the association between IL17A gene polymorphism and the risk of Bacillus Calmette-Guerin (BCG) osteitis after newborn vaccination and between IL17A gene polymorphism and IL-17A concentrations in serum. Methods IL17A rs2275913 gene polymorphisms and serum IL-17A concentrations were studied in 132 adults aged 21-49 years from across Finland, who had BCG osteitis in infancy after a newborn BCG vaccination. The subjects were recruited in 2007-2008, and their whole-blood samples were sent to the National Institute for Health and Welfare, Turku, Finland. Their genotypes and minor allele frequencies were compared with 405 population-based unvaccinated controls aged two to three months from a prospective birth cohort study. Results The genotypes and allele frequencies of IL17A rs2275913 differed significantly between the former BCG osteitis patients and controls. The genotype was variant in 75.8% of cases and 64.0% of controls (p = 0.012), and the minor allele frequency was 50.0% in the cases and 41.6% of the controls (p = 0.009). Serum IL-17 concentrations did not differ significantly between the cases with wild or variant genotypes. Conclusion IL17A rs2275913 gene polymorphism was associated with a risk of BCG osteitis after vaccination.

Interferon-gamma (IFN-γ) is a key cytokine in defense against mycobacteria, including Bacillus Calmette-Guérin (BCG). Mannose-binding lectin (MBL) and toll-like receptors (TLRs) are pattern-recognizing molecules of innate immunity. The aim of the present study was to investigate the relationship between polymorphisms in MBL, TLR1, TLR2 and TLR6 encoding genes and stimulated IFN-γ and interleukin-12 (IL-12) ex vivo production in BCG osteitis survivors.Data on single nucleotide polymorphisms in the MBL2 gene and TLR1, TLR2 and TLR6 genes were available from 132 former BCG osteitis patients, and data on ex vivo IFN-γ and IL-12 production were available from 115 and 118 patients, respectively. The present study is a secondary analysis of these available data. In an earlier study, we were able to characterize low IFN-γ and low IL-12 producers after BCG+IL-12 or BCG+IFN-γ stimulations, respectively.Three patients had the homozygous variant MBL2 genotype, and one of them was a low IFN-γ producer (both concentration and response5th percentile). The heterozygous variant MBL2 genotype showed no association with IFN-γ or IL-12 production. The TLR2 variant genotype was present in 14 subjects; 28.6% of them were low IFN-γ producers versus 7.8% of those 103 with the TLR2 wild genotype (P = 0.037). TLR1 or TLR6 polymorphisms had no significant associations with stimulated ex vivo IFN-γ or IL-12 production.Preliminary evidence was found that variant genotypes of the MBL2 gene (if homozygous) and variant genotypes of the TLR2 gene (only heterozygotes present) are associated with low IFN-γ production.

Interleukin 17A (IL-17A) is a pro-inflammatory cytokine of the IL-17 family predominantly secreted by T helper 17 cells. IL-17A is involved with the pathogenesis of inflammatory diseases such as asthma but seems to decrease the disease severity of bronchiolitis. [1] In our previous studies, the IL17A rs2275913 single nucleotide polymorphism (SNP) was associated with asthma risk at 11-13 years of age, but not earlier at 5-7 years of age, in the cohort of originally 166 children hospitalised for bronchiolitis at younger than six months of age. [2] The IL17A rs4711998 and rs8193036 SNPs were also studied and they did not show any such associations at either age. [3].

Background Interferon-γ (IFN-γ) and interleukin-12 (IL-12) play a crucial role in the defense against mycobacteria, and in the response to bacillus Calmette-Guerin (BCG) vaccination. We have previously reported clinical and outcome data of 222 BCG osteitis cases diagnosed in 1960-1988 in Finland. The immunological and genetic reports have been based on 132 blood samples obtained in 2007-2008. Methods We compared IFNγ rs2430561 and rs35314021, IL12A rs568408 and rs2243115, and IL12B rs3212227 single-nucleotide polymorphisms (SNP) between 132 BCG osteitis patients and 99 population-based controls. In addition, stimulated production of IFN-γ and IL-12 in cell culture was evaluated in relation to the presence of IFNγ and IL12 wild versus variant genotypes, respectively. Results The distributions of IFNγ rs2430561, IFNγ rs35314021, IL12A rs568408, IL12A rs2243115 and IL12B rs3212227 SNP did not differ between BCG osteitis patients and Finnish population-based controls. For IFNγ rs2430561, IFNγ rs35314021 and IL12A rs2243115, the negative result was confirmed by comparing the minor allele frequencies (MAF) in BCG osteitis cases with those in the publicly available genome aggregation database, including data for 3,472 Finnish persons. Instead, for IL12A rs568408 and IL12B rs3212227, the comparison of MAF in BCG osteitis cases with those in population-based and in aggregation-based controls gave conflicting results. The presence of the wild versus variant genotype had no significant association with IL-12 or IFN-γ production in BCG-stimulated cell cultures. Conclusion IFNγ gene polymorphisms did not show any association with BCG osteitis after newborn vaccination.

Aim The united airway disease (UAD) hypothesis suggests that allergic rhinitis and asthma develop together. We evaluated the evidence for and against the UAD hypothesis at five to seven years of age after hospitalisation for bronchiolitis at less than six months. Methods This study used prospective follow-up data for 102 children hospitalised for bronchiolitis under the age of six months. We included the presence of previous and current asthma, prolonged rhinitis and skin prick tests (SPT) to common inhaled allergens and lung function by impulse oscillometry (IOS) at five to seven years of age. Bronchial hyper-reactivity (BHR) was assessed using the exercise challenge test and bronchodilation test. Results Current asthma, but not previous transient asthma, was associated with prolonged rhinitis and a positive SPT. BHR, which reflected reactive airways, but not lung function, was associated with respiratory allergy, namely the combination of current asthma, prolonged rhinitis and a positive SPT. Conclusion This post-bronchiolitis follow-up study suggested an association between respiratory allergy and reactive airways at five to seven years of age, which supported the UAD hypothesis. However, previous transient asthma and a reduction in lung function reduction did not support the hypothesis.

Summary Background Variations in the genes that regulate innate immunity responses may be associated with susceptibility to asthma or atopy after early-life bronchiolitis. The aim of this study was to evaluate the association between four different polymorphisms of the IL-10 gene at rs1800871, rs1800872, rs1800890, and rs1800896, either alone or in combination, and post-bronchiolitis asthma or allergies at 5–7 years of age. Methods Data on single nucleotide polymorphisms (SNP) of IL-10 rs1800896 (−1082G/A), rs1800871 (−819C/T), rs1800872 (−592C/A), and IL-10 rs1800890 (−3575T/A) were available for 135 children. Polymorphisms and their associations with asthma and allergies were studied in 135 preschool-aged children who had been hospitalized for bronchiolitis at age 0–6 months. Their parents were interviewed to record the children's history with asthma and allergies from infancy to the present. Results At 6.4 years (mean), asthma was present in 17 children (12.6%), while recurrent wheezing during the first 7 years of life was present in 39 (28.9%) children. Fifty-three (39.3%) study participants had current atopy (atopic eczema or allergic rhinitis). Eight (72%) of 11 children with the IL-10 rs1800896, IL-10 rs1800871, and IL-10 rs1800872 combination AA + CT + CA had current atopy (P = 0.02 vs. 38% in other genotype combinations). Twenty-three (56%) children with the IL-10 rs1800871C/T or IL-10 rs1800872C/A genotype had present atopy versus 34 (38%) with other IL-10 genotypes (P = 0.03). Between 2 years and 3 years of age, 27% of ATA haplotype carriers had asthma versus 13.7% of other haplotype carriers (P = 0.02). Conclusions IL-10 polymorphisms at rs1800871, rs1800872, rs1800890, and rs1800896 seem to be associated with elevated allergies and/or recurrent wheezing risk in later childhood, after early-life bronchiolitis. Pediatr Pulmonol. 2016; 9999:XX–XX. © 2016 Wiley Periodicals, Inc.

Background: Infant bronchiolitis may lead to lung function reduction. However, reversibility of changes in lung function is less studied in adolescents after infant bronchiolitis. Methods: The aim of this study was to evaluate baseline and post-bronchodilator lung function at the age of 10-13 years after bronchiolitis in early infancy, with special focus on the RSV aetiology. Flow-volume spirometry with bronchodilation test was measured in 89 cases with early-life bronchiolitis and 108 controls without history of bronchiolitis at the mean age of 11.7 years. Parameters of flow-volume spirometry were analysed as sex-specific height-related %of-predicted values. We hypothesized that bronchiolitis in early infancy is associated with reduced lung function in early adolescence. Results: As continuous variables, forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) after bronchodilation was lower in cases than controls. As categorised variables, FEV1 was pathological (under the 5th percentile of the national references) in 25% of cases before bronchodilation (controls 12%, p=0.020), in 18% of cases after bronchodilation (controls 5%, p=0.003), and FEV1/FVC was pathological in 25% of cases before bronchodilation (controls 13%, p=0.034). In the adjusted logistic regression, infant bronchiolitis was associated with pathological FEV1 before (odds ratio 2.4) and after (odds ratio 4.4) bronchodilation. The result was similar in RSV positive cases. Conclusions: Evidence of reduced FEV1 before and after bronchodilation was found at 10-13 years of age after infant bronchiolitis suggesting an irreversible bronchial obstruction.

AIM Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is involved with bronchiolitis and asthma. We evaluated associations between four IL-10 polymorphisms, namely rs1800871, rs1800872, rs1800890 and rs1800896, and post-bronchiolitis asthma in young adolescents. METHODS The cohort consisted of 125 children hospitalised for bronchiolitis at Tampere University Hospital, Finland, in 2000-2004, at less than six months of age. At 11-13 years, asthma diagnoses and asthma-presumptive symptoms, allergic rhinitis and use of inhaled corticosteroids (ICS) were registered. Data on the four polymorphisms and their genotypes, haplotypes and allele frequencies were analysed in relation to asthma, allergic rhinitis and asthma medication. RESULTS The variant IL-10 rs1800896 genotype was associated with less persistent asthma at five to seven and 11-13 years of age (4.3 versus 15.2%, p = 0.04) than the wild genotype and less ICS use during the previous 12 months (5.4 versus 18.2%, p = 0.03), as was the variant allele G. Allele A was associated with more persistent asthma and ICS use. The significant differences between the variant and wild genotypes were lost in adjusted logistic regression, but the direction of the association remained. CONCLUSION IL-10 rs1800896 gene polymorphism was associated with post-bronchiolitis asthma at 11-13 years of age in children hospitalised for bronchiolitis at less than six months of age.

Background and aim Bronchiolitis is a leading cause of hospitalization in infants and is associated with a risk of subsequent asthma. The innate immunity genes, such as those encoding toll‐like receptors (TLRs), are likely to play a role in bronchiolitis and post‐bronchiolitis outcome. Thus far, only one study has considered TLR5 genes in respiratory syncytial virus (RSV) bronchiolitis. The aim of this study was to investigate the association of TLR5 gene polymorphism with virus etiology and severity of bronchiolitis, and with post‐bronchiolitis asthma. Methods We recruited 164 infants (age T) single nucleotide polymorphism, virus etiology and severity markers of bronchiolitis, and presence of post‐bronchiolitis asthma until age 11 to 13 years. Results RSV was detected in 113 (68.9%), rhinovirus in 19 (11.6%), and some other virus in 20 (12.2%) cases. Non‐RSV etiology was more common among infants with the variant CT or TT genotype in the TLR5 rs5744174 gene than in those with the CC genotype (89.7% vs 71.7%, P = 0.03). TLR5 rs5744174 polymorphism was not associated with the need of supplementary oxygen or feeding support, with the length of hospital stay, or with post‐bronchiolitis asthma at any age. Conclusion The TLR5 rs5744174 variant genotype may increase the susceptibility to bronchiolitis not caused by RSV., Background and aim: Bronchiolitis is a leading cause of hospitalization in infants and is associated with a risk of subsequent asthma. The innate immunity genes, such as those encoding toll‐like receptors (TLRs), are likely to play a role in bronchiolitis and post‐bronchiolitis outcome. Thus far, only one study has considered TLR5 genes in respiratory syncytial virus (RSV) bronchiolitis. The aim of this study was to investigate the association of TLR5 gene polymorphism with virus etiology and severity of bronchiolitis, and with post‐bronchiolitis asthma. Methods: We recruited 164 infants (age T) single nucleotide polymorphism, virus etiology and severity markers of bronchiolitis, and presence of post‐bronchiolitis asthma until age 11 to 13 years. Results: RSV was detected in 113 (68.9%), rhinovirus in 19 (11.6%), and some other virus in 20 (12.2%) cases. Non‐RSV etiology was more common among infants with the variant CT or TT genotype in the TLR5 rs5744174 gene than in those with the CC genotype (89.7% vs 71.7%, P = 0.03). TLR5 rs5744174 polymorphism was not associated with the need of supplementary oxygen or feeding support, with the length of hospital stay, or with post‐bronchiolitis asthma at any age. Conclusion: The TLR5 rs5744174 variant genotype may increase the susceptibility to bronchiolitis not caused by RSV.

Aim: Using a high‐flow nasal cannula (HFNC) for infant bronchiolitis is increasingly common, but insufficiently studied. In this retrospective study, we examined the outcomes of HFNC and compared infants who did and did not respond to this oxygen delivery method. Methods: This 2012–2015 study of six Finnish hospitals focused on 88 infants under 12 months who received HFNC: 53 on paediatric wards and 35 in paediatric intensive care units (PICUs). We reviewed patient files for underlying factors, clinical parameters and HFNC treatment. The treatment failed if the patient was transferred to another respiratory support. Results: We found HFNC treatment was successful in 76 (86%) infants, including all 53 on the paediatric wards and 23/35 PICU patients. The responders’ heart rates were significantly lower, and their oxygen saturation was significantly higher at 60 minutes after HFNC treatment started and then stayed relatively constant. Their respiratory rate was only significantly lower after 360 minutes. In non‐responders, the respiratory rate initially decreased but was higher at 180 and 360 minutes after the start of HFNC. Conclusion: We found preliminary evidence that oxygen support needs and heart rate were useful early predictors of HFNC therapy success in infants hospitalised with bronchiolitis, but respiratory rate was not.

AIM This study evaluated children hospitalised for bronchiolitis at less than six months of age to see if they had reduced lung function in early adolescence. METHODS We have prospectively followed 166 children hospitalised for infant bronchiolitis in 2001-2004 at Tampere University Hospital, Finland. At 10-13 years of age, flow-volume spirometry was measured in 89 cases and 108 controls without infant bronchiolitis from the local population register. Parameters of flow-volume spirometry before and after bronchodilation were analysed. RESULTS Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) after bronchodilation was lower in cases than controls. FEV1 was pathological - under the 5th percentile of the national references - in 25% of cases and 12% of controls (p = 0.020) before bronchodilation and in 18% of cases and 5% of controls (p = 0.003) after bronchodilation. FEV1/FVC was pathological in 25% of cases and 13% of controls (p = 0.034) before bronchodilation. Logistic regression, adjusted for current asthma and maternal smoking, showed that infant bronchiolitis was associated with pathological FEV1 before (odds ratio 2.4) and after (odds ratio 4.4) bronchodilation. The result was similar for positive respiratory syncytial virus cases. CONCLUSION Reduced FEV1 after bronchodilation was found in early adolescence after infant bronchiolitis, suggesting irreversible bronchial obstruction.

Evidence-based guidelines are needed to harmonise and improve the diagnostics and treatment of children's lower respiratory tract infections. Following a professional literature search, an interdisciplinary working group evaluated and graded the available evidence and constructed guidelines for treating laryngitis, bronchitis, wheezing bronchitis and bronchiolitis. Conclusion Currently available drugs were not effective in relieving cough symptoms. Salbutamol inhalations could relieve the symptoms of wheezing bronchitis and should be administered via a holding chamber. Nebulised adrenaline or inhaled or oral glucocorticoids did not reduce hospitalisation rates or relieve symptoms in infants with bronchiolitis and should not be routinely used.

SETTING Complications arising from bacille Calmette-Guerin (BCG) vaccination were recorded in a national register in Finland until 1988. In the period 1960-1988, 222 patients suffered from BCG osteitis. OBJECTIVE To evaluate whether single nucleotide polymorphisms (SNPs) in the promoter region of the gene encoding interleukin 10 (IL-10) are associated with BCG osteitis after vaccination in neonates. DESIGN Blood samples of 132 former BCG osteitis patients now aged 21-49 years were analysed in a controlled study for IL10 rs1800896 (-1082G/A), rs1800871 (-819C/T), rs1800872 (-592C/A) and rs1800890 (-3575T/A) polymorphisms. RESULTS The frequencies of genotypes of IL10 rs1800896, rs1800871, rs1800872 and rs1800890, the frequencies of variant genotypes and the frequencies of major or minor alleles did not differ between patients and controls. Furthermore, the frequencies of the eight possible combinations of the three IL10 alleles located close to each other (IL10 rs1800896, IL10 rs1800871 and IL10 rs1800872) were surprisingly similar. CONCLUSION Our results suggest that polymorphisms of the IL-10 encoding gene do not play a central role in the development of complications due to BCG vaccination, although the IL10 gene, especially IL10 rs1800896 (-1082G/A) polymorphism, is known to be associated with tuberculosis risk in Europeans and North Americans.

Infant bronchiolitis may be the first manifestation of asthma.To evaluate the association of early-childhood risk or protective factors for asthma and lung function reduction in adults 30 years after bronchiolitis in infancy.Forty-seven former bronchiolitis patients attended the clinical study at the median age of 29.5 years, including doctoral examination and measurement of post-bronchodilator lung function with flow-volume spirometry. Data on early-life risk factors including blood eosinophil counts on admission for bronchiolitis and on convalescence 4-6 weeks after bronchiolitis were available.Low blood eosinophil count0.25 × 10E9/l on admission for bronchiolitis was a significant protective factor and high blood eosinophil count0.45 × 10E9/l on convalescence was a significant risk factor for asthma in adulthood independently from atopic status in infancy. Parental asthma and high blood eosinophil count0.45 × 10E9/l during bronchiolitis were significant risk factors for irreversible airway obstruction (FEV1/FVC ratio below the 5th percentile lower limit of normality after bronchodilation).Our adjusted analyses confirmed that eosinopenia during infant bronchiolitis predicted low asthma risk and eosinophilia outside infection predicted high asthma risk up to the age of 28-31 years. Parental asthma and eosinophilia during bronchiolitis were recognized as risk factors for irreversible airway obstruction.

Bronchiolitis is the most common infection leading to hospitalization in infancy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and in our previous study, IL10 gene rs1800896 (− 1082A/G) polymorphism was associated with viral etiology of infant bronchiolitis. The objective of this study was to evaluate the associations between IL10 single nucleotide polymorphisms (SNPs) at rs1800890 (− 3575A/T), rs1800871 (− 819C/T) or rs1800872 (− 592C/A) either alone or combined with the SNP at rs1800896 (− 1082G/A), and the etiology and severity of infant bronchiolitis. Data on four IL10 SNPs were available from 135 full-term infants, hospitalized for bronchiolitis at age less than 6 months, and from 378 to 400 controls. Viral etiology was studied, and oxygen support, feeding support and the length of stay in hospital were recorded during bronchiolitis hospitalization. Infants with rhinovirus bronchiolitis had the IL10 rs1800890 variant AT or TT genotype less often (18.2%) than controls (63.3%, P = 0.03), and likewise, had the IL10 rs1800896 variant AG or GG genotype less often (27.3%) than controls (65.5%, P = 0.009). Twenty-eight infants with bronchiolitis had the variant–variant Grs1800896Trs1800890 haplotype, and none of them had rhinovirus infection. The IL10 rs1800871 or rs1800872 genotypes showed no associations with viruses. No association was found between any genotypes and bronchiolitis severity measures. IL10 rs1800890 and rs1800896 polymorphisms differed between infants with rhinovirus bronchiolitis and controls, but not between infants with respiratory syncytial virus bronchiolitis and controls.

Background: Toll-like receptors (TLRs) are innate immunity molecules that have an essential role in host defense and mutations in the encoding genes have been related to pathogenesis of various diseases, including asthma. Aims and objectives: The aim of this study was to examine the association between polymorphisms in the genes encoding TLR1, TLR2, TLR6 and TLR10 -- the members of TLR2 subfamily -- and asthma after infant bronchiolitis. Methods: TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 polymorphisms and their associations with post-bronchiolitis asthma, allergy and asthma medication were evaluated in 125 children aged 11-13 years who were hospitalized for bronchiolitis under the age of six months. Results: The variant genotypes of TLR1 rs5743618 and TLR10 rs4129009 genes were associated with current use of inhaled corticosteroids at age 11-13 years (OR 3.70, 95%CI 1.04-13.01 and OR 5.05, 95%CI 1.12-18.93). The results were robust to adjustments with age, gender and early-life risk factors. Conclusion: Polymorphisms in the TLR1 and TLR10 genes may increase the risk of asthma at early teenage after bronchiolitis in infancy.

Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time when universal BCG vaccinations were given to Finnish newborns. There is evidence that IL-17 plays a role in the defense against tuberculosis. The aim of this study was to evaluate the associations of IL17A rs4711998, IL17A rs8193036 and IL17A rs2275913 single-nucleotide polymorphisms (SNPs) with the risk of BCG osteitis after newborn vaccination. IL17A rs4711998, rs8193036 and rs2275913 SNPs were determined in 131 adults had presented with BCG osteitis after newborn BCG vaccination. We analyzed, using the HaploView and PLINK programs, whether allele or haplotype frequencies of these SNPs differ between the former BCG osteitis patients and Finnish population controls. Of the three IL17A SNPs studied, rs4711998 associated nominally with BCG osteitis; minor allele frequency was 0.215 in 130 BCG osteitis cases and 0.298 in 99 controls (p = 0.034). Frequency of the second common haplotype (GTA) differed significantly between BCG osteitis cases and controls (0.296 vs. 0.184, p = 0.040 after multi-testing correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination.

Background Viral aetiology of infection has a significant role in the long-term outcome of early-childhood wheezing. Objective This study examines asthma and lung function in adulthood after early-childhood wheezing induced by respiratory syncytial virus (RSV) and rhinovirus (RV). Methods A total of 100 children were hospitalized for a wheezing episode at less than 24 months of age from 1992 to 1993 in Kuopio University Hospital (Finland). Adenovirus, influenza A and B virus, parainfluenza (1-3) virus, and RSV were tested on admission using antigen detection and antibody assays, and RSV and RV were tested by polymerase chain reaction (PCR). In 2010, 49 cases and 60 population controls attended a follow-up study, which included spirometry with bronchodilation test and fractionally exhaled nitric oxide (FENO ) measurements. Results Current asthma was present in 64% of the cases with RV-induced wheezing (OR 17.0 [95%CI 3.9-75.3] vs controls), in 43% of the cases with RSV-induced wheezing episode (6.1 [1.5-24.9] vs controls), and in 12% of the controls. The RV group showed significantly higher mean FENO values than the RSV group and controls. RV-positive cases had lower MEF50 before bronchodilation and higher MEF50, FEV1, and FEV1/FVC bronchodilation responses than controls. RSV-positive cases had lower FVC than controls before bronchodilation. Conclusion Cases with RV- and RSV-induced early-childhood wheezing had increased risk for asthma in adulthood, and RV-positive cases had significantly higher FENO values than RSV-positive cases and controls. Compared to controls, RV-positive cases showed more bronchial reactivity, and RSV-positive cases showed lower FVC before bronchodilation in lung function testing. Clinical relevance Children with RV- or RSV-induced wheezing in early childhood have an increased risk for asthma and lung function abnormalities in adulthood.

Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genome-wide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish–Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p, published version, peerReviewed

Summary. Background and Aims: Obesity has been linked with asthma symptoms, need for asthma treatment andreducedlungfunctionbutnotwith increasedbronchialreactivityin children. The aim of this study was to evaluate the association between previous or current weight status andcurrentlungfunctionandbronchialreactivitytoexerciseatearlyschoolage. Methods: Ninetynine children hospitalized for bronchiolitis at the age of less than 6 months were studied with impulse oscillometry (IOS) at the mean age of 6.3 years. Data on birth weight and weight gain in infancy before hospitalization were collected during hospitalization. Current weight and height data were transformed into age- and sex-specific height-related body mass index z scores (zBMI) using the Finnish national population-based weight and height data as reference. Results: Some significantthoughonlylowor modestcorrelationswerefoundbetweencurrentzBMIandbaseline, post-exercise and post-bronchodilator IOS values in adjusted linear regression analysis. Seven obese children by zBMI had higher post-bronchodilator airway impedance (Zrs) and resistance (Rrs) at 5Hz and lower post-bronchodilator frequency dependency of resistance (dRrs/df) than normal weight children. There were no significant differences in responses to exercise or to bronchodilators between currently obese or overweight children and normal weight children. Birth weight less than 3,000g was associated with larger exercise-induced changes in Zrs and Rrs at 5Hz, and in reactance (Xrs) at 5Hz, than those with birth weight more than 3,000g. Conclusions: Preliminary evidence was found that obesity may be associated with airway obstruction, but not