Myxovirus Resistance Protein A as a Marker of Viral Cause of Illness in Children Hospitalized with an Acute Infection.

A biomarker for viral infection could improve the differentiation between viral and bacterial infections and reduce antibiotic overuse. We examined blood myxovirus resistance protein A (MxA) as a biomarker for viral infections in children with an acute infection. We recruited 251 children presenting with a clinical suspicion of serious bacterial infection, determined by need for a blood bacterial culture collection, and 14 children with suspected viral infection at two pediatric emergency departments. All children were aged between 4 weeks and 16 years. We classified cases according to the viral, bacterial, or other etiology of the final diagnosis. The ability of MxA to differentiate between viral and bacterial infections was assessed. The median blood MxA levels were 467 (interquartile range, 235 to 812) µg/L in 39 children with a viral infection, 469 (178 to 827) µg/L in 103 children with viral-bacterial coinfection, 119 (68 to 227) µg/L in 75 children with bacterial infection, and 150 (101 to 212) µg/L in 26 children with bacterial infection and coincidental virus finding (P < 0.001). In a receiver operating characteristics analysis, MxA cutoff level of 256 µg/L differentiated between children with viral and bacterial infections with an area under the curve of 0.81 (95% confidence interval [CI] = 0.73 to 0.90), a sensitivity of 74.4%, and a specificity of 80.0%. In conclusion, MxA protein showed moderate accuracy as a biomarker for symptomatic viral infections in children hospitalized with an acute infection. High prevalence of viral-bacterial coinfections supports the use of MxA in combination with biomarkers of bacterial infection. IMPORTANCE Due to the diagnostic uncertainty concerning the differentiation between viral and bacterial infections, children with viral infections are often treated with antibiotics, predisposing them to adverse effects and contributing to the emerging antibiotic resistance. Since currently available biomarkers only estimate the risk of bacterial infection, a biomarker for viral infection is needed in attempts of reducing antibiotic overuse. Blood MxA protein, which has broad antiviral activity and is rapidly induced in acute, symptomatic viral infections, is a potential biomarker for viral infection. In this diagnostic study of 265 children hospitalized because of an acute infection, blood MxA cutoff level of 256 µg/L discriminated between viral and bacterial infections with a sensitivity of 74% and specificity of 80%. MxA could improve the differential diagnostics of febrile children at the emergency department but, because of frequently detected viral-bacterial coinfections, a combination with biomarkers of bacterial infection may be needed.

Interleukin 1 receptor-like 1 rs13408661/13431828 polymorphism is associated with persistent post-bronchiolitis asthma at school age.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: IL1RL1 rs13048661/13431828 variation was associated with post-bronchiolitis asthma outcomes at school age.

Risk factors for irreversible airway obstruction after infant bronchiolitis.

BACKGROUND: 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. METHODS: 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. RESULTS: Asthma diagnosis at <12 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. CONCLUSION: 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.

Toll-interacting protein polymorphisms in viral bronchiolitis outcomes.

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.

Toll-like receptor 10 rs10004195 variation may be protective against Bacillus Calmette-Guérin osteitis after newborn vaccination.

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-Guérin (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.

IL17F rs763780 single nucleotide polymorphism is associated with asthma after bronchiolitis in infancy.

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.

IL17RA variations showed no associations with post-bronchiolitis asthma or lung function.

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.

Interleukin 17F gene variations showed no association with BCG osteitis risk after newborn 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-Guérin (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.

Interleukin-1 receptor-associated kinase-4 gene variation may increase post-bronchiolitis asthma risk.

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.

Prevalence of respiratory viruses and antiviral MxA responses in children with febrile urinary tract infection.

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 < 0.001) or virus-positive (171 [112-331] µg/L, 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.

IL33 rs1342326 gene variation is associated with allergic rhinitis at school age after infant bronchiolitis.

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.

Toll-like receptor 10 rs4129009 gene polymorphism is associated with post-bronchiolitis lung function in adolescence.

AIM: The aim was to evaluate the association of polymorphisms in the Toll-like receptor (TLR) 2 subfamily encoding genes with lung function by spirometry at 10-13 years of age in children who had been hospitalised for bronchiolitis at <6 months of age. METHODS: In a prospective cohort of 166 former bronchiolitis patients, 138 returned a structured questionnaire and 89 attended a clinical follow-up visit including spirometry before and after bronchodilation at 10-13 years of age. Data on polymorphisms of the TLR1, TLR2, TLR6 and TLR10 genes were available from 81-82 children. RESULTS: In the TLR10 rs4129009, the wild (AA) genotype was associated with lower FEV1/FVC before (92.4 vs 97.4, P = .002) and after (95.5 vs 98.6, P = .011) bronchodilator administration, compared to those with the variant genotype. When the TLR10 rs4129009 and TLR2 rs5743708 genotypes, and the TLR10 rs4129009 and TLR1 rs5743618 genotypes, respectively, were analysed as combined, both baseline and post-bronchodilator FEV1/FVC were lowest in the subjects with the wild (AA) genotype of the TLR10 rs4129009. CONCLUSION: In this post-bronchiolitis follow-up, lung function in children with the variant TLR10 rs4129009 genotype with potentially altered TLR10 function was superior to lung function in those with the wild genotype.

Toll-like receptor 4 polymorphisms were associated with low serum pro-inflammatory cytokines in BCG osteitis survivors.

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-Guérin (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.