Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

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Rationale: Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. Objective: To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. Methods: A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. Measurements and Main Results: Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). Conclusions: Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.Keywords: virus; wheezing; allergic sensitization; RSV; human rhinovirus Aeroallergen sensitization and virus-induced wheezing episodes during infancy and early childhood are risk factors for subsequent asthma development, and children with both risk factors in early life are at particularly high risk of having asthma at school age (1, 2). Understanding the sequence of events that lead to sensitization and virus-induced wheezing during early life is important to identifying potential causal relationships in the development of atopic asthma. Early allergic sensitization has consistently been identified as a risk factor for asthma development, and plausible mechanisms by which allergic sensitization leads to greater severity of viral respiratory illnesses have also been proposed (3). If allergic sensitization causes subsequent virus-induced wheezing and asthma inception, then preventing or interrupting the development of allergic sensitization would be a potential strategy for asthma prevention.In contrast to this concept, some animal models of early life infection suggest that virus infection could lead to allergic sensitization (4, 5). In clinical studies, S...

Rationale: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses. Objectives: To identify factors that influence the severity of HRV illnesses. Methods: HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI). Measurements and Main Results: Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5-to 10-fold more likely to cause MSI in the winter months (P , 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P ¼ 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%. Conclusions: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.Keywords: rhinovirus; severe illness; species; type; seasonality Human rhinoviruses (HRVs) are the most prevalent human respiratory viruses. Annually, they infect billions of people and are responsible for at least one-half of all acute upper respiratory illnesses (common colds), the most common illness of humans (1-3). In addition to common colds, infections with HRV result in a wide range of other clinical outcomes ranging from asymptomatic infection to severe lower respiratory illnesses, such as bronchiolitis, pneumonia, and exacerbations of asthma (1, 4-7). It is likely that host, viral, and environmental factors contribute to the severity of illness caused by HRV infection. Indeed, more severe HRV infections are associated with phenotypic characteristics such as extremes in age; chronic respiratory diseases such as asthma; reduced interferon responses in the blood and airway; and, in early life, male sex and reduced lung function (4,8). Little is known about viral and environmental determinants of illness severity.HRVs are a large group of genetically diverse RNA viruses and are classified phylogenetically into three species (A, B, and C). The 100 classical serotypes are found within species A and B, and approximately 50 newly identified types are HRV-Cs (5, 9-15). This tremendous genetic diversity represents a major obstacle toward developing both antivirals and vaccines for HRV, and iden...

Worldwide rates of systemic fungal infections, including three of the major pathogens responsible for such infections in North America (Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis), have soared recently, spurring interest in developing vaccines. The development of Th1 cells is believed to be crucial for protective immunity against pathogenic fungi, whereas the role of Th17 cells is vigorously debated. In models of primary fungal infection, some studies have shown that Th17 cells mediate resistance, while others have shown that they promote disease pathology. Here, we have shown that Th1 immunity is dispensable and that fungus-specific Th17 cells are sufficient for vaccine-induced protection against lethal pulmonary infection with B. dermatitidis in mice. Further, vaccine-induced Th17 cells were necessary and sufficient to protect against the three major systemic mycoses in North America. Mechanistically, Th17 cells engendered protection by recruiting and activating neutrophils and macrophages to the alveolar space, while the induction of Th17 cells and acquisition of vaccine immunity unexpectedly required the adapter molecule Myd88 but not the fungal pathogen recognition receptor Dectin-1. These data suggest that human vaccines against systemic fungal infections should be designed to induce Th17 cells if they are to be effective.

Background Detection of either viral or bacterial pathogens is associated with wheezing in children, however the influence of both bacteria and virus on illness symptoms has not been described. Objective We evaluated bacterial detection during peak RV season in children with and without asthma to determine if an association exists between bacterial infection and the severity of RV illnesses. Methods 308 children (166 with asthma, 142 without asthma) ages 4–12 years provided five consecutive weekly nasal samples during September, and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were performed on all nasal samples. Results Detection rates were 53%, 17% and 11% for H. influenzae, S. pneumoniae and M. catarrhalis, respectively, with detection of RV increasing the risk of detecting bacteria within the same sample (OR 2.0, 95% CI 1.4–2.7, p<0.0001) or the following week (OR 1.6 (1.1–2.4), p=0.02). In the absence of RV, S. pneumoniae was associated with increased cold symptoms (mean 2.7 (95% CI 2.0–3.5) vs. 1.8 (1.5–2.2), p=0.006) and moderate asthma exacerbations (18% (12%–27%) vs. 9.2% (6.7%–12%), p=0.006). In the presence of RV, S. pneumoniae was associated with increased moderate asthma exacerbations (22% (16%–29%) vs. 15% (11%–20%), p=0.01). Furthermore, M. catarrhalis detected alongside RV increased the likelihood of experiencing cold and/or asthma symptoms compared to isolated detection of RV (OR 2.0 (1.0–4.1), p=0.04). Regardless of RV status, H. influenzae was not associated with respiratory symptoms. Conclusion RV infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M. catarrhalis and S. pneumoniae contribute to the severity of respiratory illnesses, including exacerbations of asthma.

Background Early life rhinovirus (RV) wheezing illnesses and aeroallergen sensitization increase risk of asthma at school age. Whether these remain risk factors for the persistence of asthma out to adolescence is not established. Objective To define the relationships among specific viral illnesses and the type and timing of aeroallergen sensitization with the persistence of asthma into adolescence. Methods 217 children were followed prospectively from birth to age 13 years. The etiology and timing of viral wheezing illnesses during the first 3 years of life were assessed along with patterns of allergen sensitization. The associations between viral wheezing illnesses, presence and pattern of aeroallergen sensitization and asthma diagnosis at 13 years of age were evaluated. Results When adjusted for all viral etiologies, wheezing with RV [odds ratio (OR) = 3.3, 95% CI 1.5-7.1], but not respiratory syncytial virus (RSV) [OR = 1.0, 95% CI 0.4-2.3], was associated with asthma at age 13 years. Age of aeroallergen sensitization also influenced asthma risk; 65% of children sensitized by age 1 year had asthma at age 13 years, compared to 40% of children not sensitized at age 1 but sensitized by age 5, and 17% of children not sensitized at age 5. Early life aeroallergen sensitization and RV wheezing had additive effects on asthma risk at adolescence. Conclusion In a high-risk birth cohort, the persistence of asthma at 13 years of age was most strongly associated with outpatient wheezing illnesses with RV and aeroallergen sensitization in early life.

To better understand the viral aetiology of recurrent and prolonged illnesses, nasal secretions were prospectively collected from 285 infants at increased risk of developing asthma. Of these, 27 infants had recurrent (at least five) moderate-to-severe respiratory illnesses (MSIs). The viral aetiology of the 150 MSIs and 86 scheduled visits was analysed by molecular diagnostics. The demographic and clinical data were compared with infants who had 0-4 MSIs.Frequently ill infants had higher exposure to other children and more wheezing illnesses than less symptomatic children. Viruses were detected in 136 (91%) out of 150 MSIs, 14 (67%) out of 21 mild illnesses and 29 (45%) out of 65 asymptomatic visits. Human rhinovirus was the most common aetiological agent (61, 43 and 35% in MSIs, mild illnesses and asymptomatic visits, respectively). Mixed viral infections were generally associated with more severe illnesses (27, 0 and 5%, respectively). Among the 27 frequently ill infants, only eight (5.3%) out of 150 MSIs were prolonged (o2 weeks duration). Considering all samples, detection of the same virus strain o2 weeks apart was unusual (5.3% of all 244 positive findings).Human rhinovirus infections occur early, pervasively and repetitively in these high-risk infants. Infants with prolonged or recurrent respiratory illnesses most often have a series of infections rather than persistent infection with one virus strain.