ENHANCED NEUTRALIZING ANTIBODY RESPONSES TO RHINOVIRUS C AND AGE-DEPENDENT PATTERNS OF INFECTION

Rationale: Rhinovirus C (RV-C) can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Methods: Longitudinal data from the Childhood Origins of ASThma (COAST) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for rhinovirus A (RV-A) and RV-C (3 types each) were determined using a novel polymerase chain reaction-based assay. We pooled data from 14 study cohorts in the United States, Finland, and Australia and used mixed-effects logistic regression to identify factors related to the proportion of RV-C versus RV-A detection. Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, while RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (p<0.001, chi-square) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5%-27%) at age 2 years, but by age 16, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A, p<0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (p<0.0001), CDHR3 genotype (p<0.05), and wheezing illnesses (p<0.05). Furthermore, certain RV types (e.g., C2, C11, A78, A12) were consistently more virulent and prevalent over time. Discussion: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.Rinovirukset (RV) ovat yleisiä hengitystieinfektioiden aiheuttajia. Nuorilla lapsilla rinovirusinfektiot voivat vaatia jopa tehohoitoa. Rinoviruslajeja on kolme (A, B ja C) ja näiden alatyyppejä on 160. Lasten rinovirusinfektioista yleisimmät ovat RV-A ja RV-C. Alttiuteen sairastaa RV-C infektio vaikuttavat useat tekijät, joista yksi esimerkki on CDHR3-geenin polymorfismi (rs6967330). Tutkimuksissa on todettu RV-C:n esiintyvyyden olevan lapsuudessa suurempaa kuin aikuisuudessa suhteessa RV-A:n esiintyvyyteen. Rinovirusinfektiot aiheuttavat spesifisiä vasta-ainereaktioita, joiden myötä uusintainfektion riski pienenee. RV-C:n suhteen neutraloivien vasta-ainereaktioiden muodostumista ei ole pystytty aiemmin tutkimaan puutteellisten in vitro -järjestelmien vuoksi. Tämän tutkimuksen tavoitteena on tunnistaa miten ikä ja muut yksilötason tekijät ovat yhteydessä RV-C-infektion sairastuvuuteen sekä taudin vaikeuteen. Lisäksi tutkitaan, liittyykö RV-C-infektioiden vähäisempi esiintyvyys iän myötä lisääntyneisiin neutraloiviin vasta-ainereaktioihin RV-C:tä vastaan. Iän ja RV-C-infektion välistä yhteyttä tutkittiin COAST syntymäkohorttitutkimuksen pitkittäisdatasta. RV-A ja RV-C-spesifisiä neutraloivia vasta-aineita määrittämään käytettiin uuden laista PCR-pohjaista menetelmää. Lisäksi dataan on yhdistetty lisäksi 14 tutkimuskohorttia USA:sta, Suomesta ja Australiasta. Tutkimuksessa on käytetty sekamallista logistista regressioanalyysia tunnistamaan tekijöitä, jotka liittyvät RV-C: suhteellisen osuuden tunnistamiseen RV-A:sta. COAST-kohortissa RV-A ja RV-C olivat yhtä yleisiä pikkulapsilla, mutta vanhemmilla lapsilla RV-C:n esiintyvyys oli suurempaa kuin RV-A:n esiintyvyys sekä ylähengitysteiden yhteydessä että jo ennalta suunnitelluilla seurantakäynneillä (p<0.001). Kahden vuoden iässä RV-A- tai RV-C-lajien neutraloivien vasta-aineiden esiintyvyys oli matala (5–27 %), mutta 16 ikävuoteen mennessä RV-C-seropositiivisuutta esiintyi enemmän (78% vs. 18%, p<0.0001). Yhdistelmäanalyysissä RV-C RV-A suhde sairauden yhteydessä oli tilastollisesti merkitsevästi riippuvainen iästä, CDHR3-genotyypistä sekä uloshengityksen vinkunaa aiheuttavista sairauksista (p<0.05). Lisäksi tietyt RV-tyypit (esim. C2, C11, A78 ja A12) olivat virulentimpia sekä yleisimmin esiintyviä ajan mittaan. Tutkimuksen myötä tiedetään enemmän RV-tyyppien esiintyvyydestä ja vasta-ainereaktioista. Parempi ymmärrys iän ja genetiikan suhteen riskissä olevista potilaista voi ohjata rokotteiden tai muiden uusien hoitojen kehitystä

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode

Background Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta(2)-agonist in this clinical scenario. Objective To study post hoc the short-term (up to 2 months) efficacy of inhaled beta(2)-agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children. Methods The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2-4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences. Results Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group x treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p .26). Conclusions In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.Peer reviewe

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode

BackgroundAcute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta2-agonist in this clinical scenario.ObjectiveTo study post hoc the short-term (up to 2 months) efficacy of inhaled beta2-agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children.MethodsThe study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2–4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences.ResultsMedian age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p p > .26).ConclusionsIn young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.</p

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection

Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.Longitudinal data from the Childhood Origins of ASThma (COAST) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for rhinovirus A (RV-A) and RV-C (3 types each) were determined using a novel polymerase chain reaction-based assay. We pooled data from 14 study cohorts in the United States, Finland, and Australia and used mixed-effects logistic regression to identify factors related to the proportion of RV-C versus RV-A detection.In COAST, RV-A and RV-C infections were similarly common in infancy, while RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (pRhinovirus C (RV-C) can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.</div

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.

RATIONALE: Rhinovirus C (RV-C) can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. OBJECTIVES: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. METHODS: Longitudinal data from the Childhood Origins of ASThma (COAST) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for rhinovirus A (RV-A) and RV-C (3 types each) were determined using a novel polymerase chain reaction-based assay. We pooled data from 14 study cohorts in the United States, Finland, and Australia and used mixed-effects logistic regression to identify factors related to the proportion of RV-C versus RV-A detection. MEASUREMENTS AND MAIN RESULTS: In COAST, RV-A and RV-C infections were similarly common in infancy, while RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (p\u3c0.001, chi-square) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5%-27%) at age 2 years, but by age 16, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A, p\u3c0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (p\u3c0.0001), CDHR3 genotype (p\u3c0.05), and wheezing illnesses (p\u3c0.05). Furthermore, certain RV types (e.g., C2, C11, A78, A12) were consistently more virulent and prevalent over time. DISCUSSION: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types

Enhanced neutralizing antibody responses to rhinovirus C and age-dependent patterns of infection

Abstract Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection. Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P &lt; 0.001, χ²) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5–27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P &lt; 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P &lt; 0.0001), CDHR3 genotype (P &lt; 0.05), and wheezing illnesses (P &lt; 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time. Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen