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 (n5128; 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 (n576) had higher asthma severity scores than children whose HRV infection was HRVA or HRVB only (n534; p50.018), and all other children (n550; p50.016). 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.

Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated “exhausted” phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcεR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R+ alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-α can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.

Rationale: Human rhinovirus species C (HRV-C) is the most common cause of acute wheezing exacerbations in young children presenting to hospital, but its impact on subsequent respiratory illnesses has not been defined. Objectives: To determine whether acute wheezing exacerbations due to HRV-C are associated with increased hospital attendances due to acute respiratory illnesses (ARIs). Methods: Clinical information and nasal samples were collected prospectively from 197 children less than 5 years of age, presenting to hospital with an acute wheezing episode. Information on hospital attendances with an ARI before and after recruitment was subsequently obtained. Measurements and Main Results: HRV was the most common virus identified at recruitment (n ¼ 135 [68.5%]). From the 120 (88.9%) samples that underwent typing, HRV-C was the most common HRV species identified, present in 81 (67.5%) samples. Children with an HRV-related wheezing illness had an increased risk of readmission with an ARI (relative risk, 3.44; 95% confidence interval, 1.17-10.17; P ¼ 0.03) compared with those infected with any other virus. HRV-C, compared with any other virus, was associated with an increased risk of a respiratory hospital admission before (49.4% vs. 27.3%, respectively; P ¼ 0.004) and within 12 months (34.6% vs. 17.0%; P ¼ 0.01) of recruitment. Risk for subsequent ARI admissions was further increased in atopic subjects (relative risk, 6.82; 95% confidence interval, 2.16-21.55; P ¼ 0.001). Admission risks were not increased for other HRV species. Conclusions: HRV-C-related wheezing illnesses were associated with an increased risk of prior and subsequent hospital respiratory admissions. These associations are consistent with HRV-C causing recurrent severe wheezing illnesses in children who are more susceptible to ARIs. Keywords: human rhinovirus; acute wheezing illnesses; hospital admissions; pediatricsNumerous studies have demonstrated that wheezing associated with certain viruses in early childhood is an independent risk factor for subsequent wheezing illnesses and the development of asthma (1-7). Most earlier reports focused on respiratory syncytial virus (RSV) bronchiolitis in infancy and recurrent wheezing (1-3, 8, 9), but more recent research has shown that wheezing episodes due to human rhinovirus (HRV) have a stronger association than RSV with further wheezing episodes and asthma in early childhood (4,5,7,9).Previously, HRV-A and -B (10-12) were the only known HRV species, but improved virological detection methods using polymerase chain reaction (PCR) and sequencing (13-15) have revealed another species of rhinovirus, C (16,17). A number of studies have shown that HRV-C is the most common HRV species associated with acute asthma attacks severe enough to result in children presenting to hospital (18-21), and further studies have shown that it also causes more severe asthma attacks than other rhinoviruses (22) and all other viruses (23).These studies raise the issue of whether HRV-C also influences subsequent acute wheezing e...

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7 hi versus IRF7 lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-g. The two phenotypes also produced distinct clinical phenotypes. For IRF7 lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7 hi versus IRF7 lo phenotypes with associated differences in clinical phenotypes.

The ST2 gene is a member of the interleukin-1 receptor family and is located on chromosome 2q12, an area of the genome that has been associated with asthma. The soluble product of the ST2 gene, serum ST2 (sST2), has previously been shown to be elevated in adult asthmatic patients. This study investigated the potential role of ST2 in children with acute asthma. Children aged 2-16 years (n = 186) were recruited on presentation with acute asthma in the emergency department. Blood was obtained on presentation and during convalescence. Variables assessed included sST2 levels, a comprehensive assembly of clinical parameters and two polymorphisms in the ST2 gene, -26999G/A, located in the distal promoter region, and ala78glu polymorphism, on exon 3. The A allele of the -26999G/A polymorphism occurred more frequently in asthmatics compared with an unselected control group (P = 0.031). Serum ST2 levels were substantially higher during acute asthma compared with levels after the attack: 0.29 ng/ml (95% confidence interval: 0.23-0.36) and 0.14 ng/ml (0.12-0.17), respectively (P = 0.001) and were inversely related to eosinophil counts during an acute asthma attack (P = 0.002). The -26999AA genotype, as well as the AC haplotype, was associated with asthma severity scores (P = 0.05 and 0.02) compared with the -26999GA and GG genotypes. Serum ST2 levels were not associated with any of the studied genotypes or haplotypes. The observed associations of ST2 genotypes and haplotypes with acute asthma and asthma severity scores as well as the phenotypic differences associated with ST2 polymorphisms suggest that ST2 may play a role in the pathophysiology of asthma.

Respiratory virus infections account for a significant proportion of acute admissions to the paediatric intensive care unit (PICU). Recent studies have shown that rhinoviruses (RV) are the most frequent virus detected in severe cases of acute respiratory illnesses (ARI) admitted to a PICU. The aim of this study was to determine the prevalence of different viruses, in particular RV species, in children with ARI admitted to a tertiary PICU. Nasopharyngeal aspirates (NPA) from 229 children admitted to PICU with an ARI were analysed. RV was the most common virus detected, being present in 94 (41.0%) of samples examined, followed by respiratory syncytial virus (RSV) which was identified in 50 (21.8%) samples. A subsection analysis of cases with residual sample available of sufficient quality to allow for RV species typing showed that overall, the percentage of PICU admissions for each RV species was 22.3% for RV-C, 17.5% for RV-A and 1.7% for RV-B. This study demonstrated that RV is the most frequent virus identified in children admitted to a tertiary PICU with an ARI and RV-C is the most common RV species detected. Importantly, in the children admitted to PICU with an ARI, RV-C was by itself as common a pathogen as RSV.

The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species.

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.