High fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations: A prospective cohort study.

BACKGROUND: The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown. OBJECTIVE: To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma. METHODS: Stable asthmatics had spirometry, skin prick test, measurement of FeNO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR. RESULTS: A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation (HR 7.6 95% CI: 1.6-35.2, P=.010) as did having FeNO >25 ppb (HR 3.4 95% CI: 1.1-10.4, P=.033). CONCLUSION AND CLINICAL RELEVANCE: Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and FeNO, could be included in the risk assessment of patients with asthma in future studies.

Lower anti-echovirus antibody responses in children presenting to hospital with asthma exacerbations.

BACKGROUND: Rhinoviruses from the Enterovirus genus cause frequent infections and induce remarkably high titres of anticapsid antigen antibodies in asthmatics, while the prevalence of neutralising antibodies to the gut-trophic echoviruses from the same genus is diminished. OBJECTIVE: To assess the absolute and specific antibody titres to VP1 antigens of the gut-trophic enteroviruses, echovirus 30 and Sabin 1 poliovirus, in asthmatic and non-asthmatic children. METHODS: Recombinant polypeptides representing the VP1 capsid antigens of echovirus 30 and Sabin poliovirus 1 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n = 45) and non-asthmatic (n = 29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. RESULTS: The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls (P < 0.05) and inversely correlated with total IgE levels for the whole study population (r = -0.262; P < 0.05). There was no difference in the prevalence and titre between groups to the VP1 antigen of Sabin poliovirus. Anti-tetanus toxoid titres measured for comparison did not correlate with anti-echovirus or poliovirus, but correlated with anti-rhinovirus titres in controls but not asthmatics, where the titres were higher for the asthmatic group. CONCLUSIONS AND CLINICAL RELEVANCE: The associations of lower antibody titres of asthmatic children to echovirus reported here and those of our previous findings of a heightened response to rhinovirus suggest a dichotomy where respiratory enterovirus infection/immunity increases the probability of developing asthma and enteric infections lower the risk. This provides further support for the concept of intestinal infection playing a key role in the development of allergic respiratory disease.

Association between human rhinovirus C and severity of acute asthma in children.

A new and potentially more pathogenic group of human rhinovirus (HRV), group C (HRVC), has recently been discovered. We hypothesised that HRVC would be present in children with acute asthma and cause more severe attacks than other viruses or HRV groups. Children with acute asthma (n = 128; age 2-16 yrs) were recruited on presentation to an emergency department. Asthma exacerbation severity was assessed, and respiratory viruses and HRV strains were identified in a nasal aspirate. The majority of the children studied had moderate-to-severe asthma (85.2%) and 98.9% were admitted to hospital. HRV was detected in 87.5% and other respiratory viruses in 14.8% of children, most of whom also had HRV. HRVC was present in the majority of children with acute asthma (59.4%) and associated with more severe asthma. Children with HRVC (n = 76) had higher asthma severity scores than children whose HRV infection was HRVA or HRVB only (n = 34; p = 0.018), and all other children (n = 50; p = 0.016). Of the 19 children with a non-HRV virus, 13 had HRV co-infections, seven of these being HRVC. HRVC accounts for the majority of asthma attacks in children presenting to hospital and causes more severe attacks than previously known HRV groups and other viruses.

The importance of environment on respiratory genotype/phenotype relationships in the Inuit.

BACKGROUND: Genetic and environmental influences and their interactions are central to asthma pathogenesis. This study aimed to investigate the effects of different macro-environments on asthma genotype-phenotype associations in two geographically separated populations with common ancestry. METHODS: To accomplish this, two unselected populations of Inuit were recruited, one living in Greenland (n = 618) and the other in Denmark (n = 739). Subjects were genotyped for CD14 C-159T, SCGB1A1 A38G, ADRB2 Arg16Gly and Gln27Glu. The resulting genetic data were analysed for relationships with asthma-related parameters including lung function, ever asthma, atopy, rhinitis and dermatitis. RESULTS: The results showed contrasting magnitude and direction of genetic associations between the two geographically separate Inuit populations. In Greenland, the ADRB2 16Arg allele was associated with male-specific lower lung function, but in Denmark the same allele was associated with male-specific higher lung function. This allele was also associated with higher incidence of ever asthma in Denmark but not in Greenland. The SCGB1A1 38A allele was associated with lower rhinitis prevalence in Greenland but not in Denmark. CONCLUSIONS: These associations suggest that environment interacts with candidate asthma genes to modulate asthma pathogenesis in the Inuit.

Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation.

BACKGROUND: Atopic sensitization to the house dust mite (HDM) is associated with altered antibody responses to the nasopharyngeal colonizing bacterium Haemophilus influenzae and children admitted to the emergency department for asthma exacerbation have reduced IgG responses to HDM allergens. OBJECTIVE: To investigate anti-bacterial and anti-allergen antibody responses during convalescence from asthma exacerbation and differences found in exacerbations associated with and without viral infection. RESULTS: IgE antibodies to the P6 bacterial antigen increased in 60% of sera during convalescence and for many children achieved titres as high as IgE titres to allergens. In contrast IgE anti-HDM titres declined during convalescence. The anti-bacterial IgE titres were the same in subjects with and without virus infection while the anti-HDM IgE declined more rapidly in virus-infected subjects. IgG titres to the major HDM allergens showed no consistent increase and the overall IgG anti-HDM titres even declined in subjects without a virus infection. Anti-bacterial IgG antibodies in contrast to IgE did not change. Patients with frequent episodic or persistent asthma had similar IgE anti-bacterial titres to patients with infrequent asthma during the acute phase, although they had reduced IgG titres to both the bacteria and the HDM. CONCLUSIONS: During the period following an acute exacerbation of asthma there was a marked and specific increase in anti-bacterial IgE compared with a reduced IgE response to HDM. This provides further support for the concept of T-helper type 2 responses to bacterial antigens playing a role in asthma pathogenesis.

Opposite gene by environment interactions in Karelia for CD14 and CC16 single nucleotide polymorphisms and allergy.

BACKGROUND: Finnish Karelians have a higher prevalence of allergic disease than Russian Karelians. As both populations are generally from the same ethnic group, the Karelian population offers a unique opportunity to analyse genetic and allergic disease interactions between 'Western' and 'Eastern' environments. OBJECTIVES: We investigated associations between allergic diseases and CD14 and CC16 polymorphisms in Finnish vs Russian Karelian women. METHODS: Adult female Karelians (330 Finnish and 274 Russian) were recruited, examined for a range of symptoms and conditions including rhinitis, itchy rash, asthma and atopy and genotyped for CD14 C-159T and CC16 A38G. RESULTS: For both CD14 C-159T and CC16 A38G, the risk allele for atopic phenotypes in Finnish Karelia was the protective allele in Russian Karelia. For CD14 C-159T, an interactive effect on ever itchy rash (P(interaction) = 0.004), itchy rash <12 mo (P(interaction) = 0.001) and dry cough at night in the past 12 months (<12 months) (P(interaction) = 0.011) was found; the risk allele was C in Russians and T in Finns. For CC16 A38G, an interaction was significant for ever rhinitis (P(interaction) = 0.006), rhinitis <12 mo (P(interaction) = 0.004), and marginally significant for ever hayfever (P(interaction) = 0.07), allergic eye symptoms <12 mo (P(interaction) = 0.09); their risk allele was G in Russians and A in Finns. CONCLUSION: An Eastern vs Western environment appears to exert an effect via opposite alleles on risk of allergic diseases in adult women.

Beta2-Adrenoceptor polymorphisms and asthma phenotypes: interactions with passive smoking.

The aim of the present study was to assess the effects of possible interactions between beta(2)-adrenoceptor gene polymorphisms and passive smoking on forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC) and exhaled nitric oxide (eNO) in children aged 11 yrs. A cross-sectional analysis of the longitudinal cohort was conducted for associations between beta(2)-adrenoceptor gene polymorphisms and lung function and eNO with regard to passive smoking. Among children exposed to tobacco smoke, those with Arg16 (at least one Arg allele) exhibited lower adjusted mean FEV(1) (2.19 versus 2.38 L) and FVC (2.43 versus 2.64 L) than Gly16 homozygotes. Those with Gln27 (at least one Gln allele) also exhibited a lower adjusted mean FEV(1) relative to Glu27 homozygotes (2.24 versus 2.39 L). Among children with no exposure to smoking, those with Arg16 or Gln27 showed lower adjusted geometric mean eNO levels compared with Gly16 homozygotes (15.4 versus 30.9 ppb) and Glu27 homozygotes (18.0 versus 49.7 ppb). In conclusion, passive smoking had a significant effect on associations between beta(2)-adrenoceptor gene polymorphisms and asthma-related phenotypes, enhancing the relationship between Arg16 and lung function and removing the relationship between Arg16 or Gln27 and exhaled nitric oxide levels.

Association of haplotypes of beta2-adrenoceptor polymorphisms with lung function and airway responsiveness in a pediatric cohort.

We evaluated the influence of haplotypes of beta(2)-adrenergic receptor (ADRB2) polymorphisms on lung function and airway responsiveness (AR) in a pediatric cohort recruited before birth and followed up to 11 years of age. The subjects (180) were the participants in a prospective study of lung function and AR. They have been assessed five times (at 1 month, 6 months, 12 months, 6 and 11 years of age) for lung function and AR. The two ADRB2 single nucleotide polymorphisms (SNPs): Arg16Gly and Gln27Glu were genotyped by PCR-RLFP and their haplotypes inferred using the program PHASE. An association between the haplotype arg16gln27 and the prevalence of positive AR was found at age 6 years (P = 0.009). The gly16gln27 haplotype was associated with higher FEV1 (P = 0.015) at age 6 and both higher FEV1 and FVC (P = 0.018 and P = 0.001, respectively) at age 11. In contrast, arg16gln27 was associated with both lower FEV1 and FVC (P = 0.028 and P = 0.011, respectively) at age 11. Children with the gly16gln27 haplotype were less likely to have asthma-ever or doctor-diagnosed asthma at age 11 (OR: 0.38; P = 0.019 and OR: 0.31; P = 0.041, respectively). In conclusion, haplotypes of beta(2)-adrenoceptor polymorphisms are associated with lung function, AR, and asthma susceptibility in childhood.

Association of CD14 promoter polymorphism with otitis media and pneumococcal vaccine responses.

Innate immunity is of particular importance for protection against infection during early life, when adaptive immune responses are immature. CD14 plays key roles in innate immunity, including in defense against pathogens associated with otitis media, a major pediatric health care issue. The T allele of the CD14 C-159T polymorphism has been associated with increased serum CD14 levels. Our objective was to investigate the hypothesis that the CD14 C-159T allele is protective against recurrent acute otitis media in children. The association between the CD14 promoter genotype and the number of acute otitis media episodes was evaluated both retrospectively and prospectively in a cohort of 300 children. Serotype-specific immunoglobulin G (IgG) antibody responses after pneumococcal vaccinations were examined according to CD14 genotype to compare immune responsiveness across genotypes. An age-dependent association was found: compared with that for CC homozygotes aged between 12 to 24 months, TT homozygotes had fewer episodes of acute otitis media (79 versus 41%, respectively; P = 0.004); this relationship was absent in older children. Additionally, TT homozygotes showed higher serotype-specific anti-pneumococcal IgG antibody levels. Our data suggest that genetic variation in CD14, a molecule at the interface of innate and adaptive immune responses, plays a key role in the defense against middle ear disease in childhood and in pneumococcal vaccine responsiveness. These findings are likely to be important to these and other immune-mediated outcomes in early life.

beta2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children.

BACKGROUND: We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function. OBJECTIVE: The current study aimed to determine whether the Arg16Gly polymorphism of the beta2 adrenoceptor (beta2AR) gene was important to this relationship. METHODS: A cohort that initially numbered 253 individuals underwent assessments of AR and lung function aged 1 month, 6 and 11 years; genotyping for polymorphisms of the beta(2)AR was performed. RESULTS: At 1 month of age, the genotype homozygous Arg16 (n=24) was associated with a mean increase in log dose-response slope (AR) of 0.27 [95% confidence interval (CI) 0.07, 0.49] compared with the genotype homozygous Gly16 (n=58), P=0.01. At 11 years of age, the genotype homozygous Arg16 (n=35) was associated with a mean reduction in the percentage of forced expiratory volume in 1 s of 5.3% [95% CI 0.3, 10.2] compared with the genotype homozygous Gly16 (n=65), P=0.03. There was no association between the Arg16Gly polymorphism and atopy or diagnosed asthma. However, nine of 69 individuals with the genotype homozygous Gly16 were admitted to hospital with asthma compared with five out of 111 individuals with the remaining genotypes (P<0.05). CONCLUSION: The Arg16Gly polymorphism may be important to the association between increased AR in infancy and reduced lung function in childhood and may also be a determinant of asthma severity in children but not asthma per se.