E. Kathryn Miller

A novel group of rhinoviruses is associated with asthma hospitalizations

Background Although recent studies have identified new group C human rhinoviruses (HRVCs), their spectrum of pediatric disease is unknown. Objective We sought to determine the presentation and burden of disease caused by HRVCs among young hospitalized children. Methods We conducted prospective population-based surveillance in 2 US counties among children less than 5 years of age hospitalized with acute respiratory illness or fever from October 2001 through September 2003. Nasal/throat swabs were obtained and tested for HRVs, as determined by means of RT-PCR and then characterized by means of partial sequencing. Results Of 1052 children enrolled and tested during the 2-year period, 167 (16%) had HRVs detected. Of 147 samples successfully sequenced, 64 were group A HRVs, 6 were group B HRVs, and 77 were HRVCs. Children with HRVCs were significantly more likely than those with group A HRVs to have underlying high-risk conditions, such as asthma (42% vs 23%, P = .023) and to have had a discharge diagnosis of asthma (55% vs 36%, P = .022). Conclusions Overall, HRVCs were detected in 7% of children hospitalized for fever or respiratory conditions and constituted almost half of all rhinovirus-associated hospitalizations, suggesting that this novel group causes a substantial burden of pediatric disease.

Rhinovirus-Associated Hospitalizations in Young Children

Abstract Background. Rhinoviruses frequently cause the common cold but have not been considered important causes of acute respiratory hospitalizations in children. Methods. A population-based surveillance study was performed among children <5 years of age who were hospitalized with respiratory symptoms or fever and who resided within counties encompassing Nashville, Tennessee, or Rochester, New York, from October 2000 through September 2001. Data collected included questionnaires, nasal and throat swabs for viral culture and polymerase chain reaction testing, and chart review. Rates of rhinovirus-associated hospitalizations were calculated. Results. Of 592 children enrolled, 156 (26%) were rhinovirus positive, representing 4.8 (95% confidence interval [CI], 4.3–5.2) rhinovirus-associated hospitalizations/1000 children. Age-specific rates per 1000 children were 17.6 (95% CI, 14.9–20.6) for 0–5-month-olds, 6.0 (95% CI, 5.0–7.0) for 6–23-month-olds, and 2.0 (95% CI, 1.6, 2.4) for 24–59-month-olds (P<.01) Children with a history of wheezing/asthma had significantly more rhinovirusassociated hospitalizations than those without a history (25.3/1000 children [95% CI, 21.6–29.5/1000 children] vs. 3.1/1000 children [95% CI, 2.7–3.5/1000 children]). Conclusions. Rhinoviruses were associated with nearly 5 hospitalizations/1000 children <5 years of age and were highest in children with a history of wheezing/asthma.

Human Rhinovirus Species Associated With Hospitalizations for Acute Respiratory Illness in Young US Children

BACKGROUND The contribution of human rhinovirus (HRV) to severe acute respiratory illness (ARI) is unclear. OBJECTIVE To assess the association between HRV species detection and ARI hospitalizations. METHODS Children <5 years old hospitalized for ARI were prospectively enrolled between December 2003 and April 2005 in 3 US counties. Asymptomatic controls were enrolled between December 2003 and March 2004 and between October 2004 and April 2005 in clinics. Nasal and throat swab samples were tested for HRV and other viruses (ie, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, and influenza virus) by reverse-transcription-polymerase chain reaction, and genetic sequencing identified HRV species and types. HRV species detection was compared between controls and patients hospitalized during months in which controls were enrolled. RESULTS A total of 1867 children with 1947 ARI hospitalizations and 784 controls with 790 clinic visits were enrolled and tested for HRV. The HRV-A detection rate among participants ≥24 months old was 8.1% in the hospitalized group and 2.2% in the control group (P = .009), and the HRV-C detection rates among those ≥6 months old were 8.2% and 3.9%, respectively (P = .002); among younger children, the detection rates for both species were similar between groups. The HRV-B detection rate was ≤1%. A broad diversity of HRV types was observed in both groups. Clinical presentations were similar among HRV species. Compared with children infected with other viruses, children with HRV detected were similar for severe hospital outcomes and more commonly had histories or diagnoses of asthma or wheezing. CONCLUSIONS HRV-A and HRV-C were associated with ARI hospitalization and serious illness outcomes.

Influenza Burden for Children With Asthma

OBJECTIVE. The goal was to estimate the influenza disease burden among children with asthma and among healthy children by using active, laboratory-confirmed, population-based surveillance. METHODS. Children 6 to 59 months of age residing in 3 US counties who were hospitalized with acute respiratory illnesses or fever were enrolled prospectively from 2000 through 2004. Similar children who presented to clinics and emergency departments during 2 of the influenza seasons (2002–2004) were enrolled. Rates of influenza-attributable outpatient visits and hospitalizations for children with asthma and for healthy children were estimated. History of asthma and receipt of influenza vaccine for the study children were determined through parental report. The prevalence of asthma in the surveillance population was assumed to be 6.2% for children 6 to 23 months of age and 12.3% for children 24 to 59 months of age. RESULTS. Of 81 children 6 to 59 months of age with influenza-confirmed hospitalizations in 2000 to 2004, 19 (23%) had asthma. Average annual influenza-attributable hospitalization rates were significantly higher among children with asthma than among healthy children 6 to 23 months of age (2.8 vs 0.6 cases per 1000 children) but not children 24 to 59 months of age (0.6 vs 0.2 case per 1000 children). Of 249 children 6 to 59 months of age with influenza-confirmed outpatient visits in 2002 to 2004, 38 (15%) had asthma. Estimated outpatient influenza-attributable visit rates were higher among children with asthma than among healthy children 6 to 23 months of age (316 vs 152 cases per 1000 children) and 24 to 59 months of age (188 vs 102 cases per 1000 children) in 2003 to 2004. Few parents reported that their children had been vaccinated, including <30% of children with asthma. CONCLUSION. Influenza-attributable health care utilization is high among children with asthma and is generally higher than among healthy children.

Human rhinovirus C associated with wheezing in hospitalised children in the Middle East.

BACKGROUND Few studies have investigated the disease burden and genetic diversity of human rhinoviruses (HRVs) in developing countries. OBJECTIVES To assess the burden of HRV in Amman, Jordan, and to characterise clinical differences between HRV groups. STUDY DESIGN We prospectively studied children <5 years, hospitalised with respiratory symptoms and/or fever in Amman, Jordan. Viruses were identified by real-time reverse transcriptase polymerase chain reaction (RT-PCR). VP4/VP2 gene sequencing was performed on HRV-positive specimens. RESULTS Of the 728 enrolled children, 266 (37%) tested positive for picornaviruses, 240 of which were HRV. Of the HRV-positive samples, 62 (26%) were of the recently identified group HRVC, 131 (55%) were HRVA and seven (3%) were HRVB. The HRVC strains clustered into at least 19 distinct genotypes. Compared with HRVA-infected children, children with HRVC were more likely to require supplemental oxygen (63% vs. 42%, p=0.007) and, when co-infections were excluded, were more likely to have wheezing (100% vs. 82%, p=0.016). CONCLUSIONS There is a significant burden of HRV-associated hospitalisations in young children in Jordan. Infection with the recently identified group HRVC is associated with wheezing and more severe illness.

Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years.

Background: Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness (URI) in infants are limited. Methods: This prospective cohort enrolled previously healthy term infants during inpatient or outpatient visits for acute URI or bronchiolitis during September to May 2004 to 2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time reverse-transcriptase polymerase chain reaction. Results: Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup and 27% URI. Among infants with bronchiolitis, 76% had respiratory syncytial virus (RSV), 18% human rhinovirus (HRV), 10% influenza, 2% coronavirus, 3% human metapneumovirus and 1% parainfluenza virus. Among infants with croup, 39% had HRV, 28% parainfluenza virus, 28% RSV, 11% influenza, 6% coronavirus and none human metapneumovirus. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% parainfluenza virus and 4% human metapneumovirus. Individual viruses exhibited distinct seasonal, demographic and clinical expression. Conclusions: The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

RATIONALE Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

Human Rhinoviruses in Severe Respiratory Disease in Very Low Birth Weight Infants

Objectives: To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants. Methods: A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction. Results: Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed. Conclusions: HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants.

Real-world comparison of two molecular methods for detection of respiratory viruses

BackgroundMolecular polymerase chain reaction (PCR) based assays are increasingly used to diagnose viral respiratory infections and conduct epidemiology studies. Molecular assays have generally been evaluated by comparing them to conventional direct fluorescent antibody (DFA) or viral culture techniques, with few published direct comparisons between molecular methods or between institutions. We sought to perform a real-world comparison of two molecular respiratory viral diagnostic methods between two experienced respiratory virus research laboratories.MethodsWe tested nasal and throat swab specimens obtained from 225 infants with respiratory illness for 11 common respiratory viruses using both a multiplex assay (Respiratory MultiCode-PLx Assay [RMA]) and individual real-time RT-PCR (RT-rtPCR).ResultsBoth assays detected viruses in more than 70% of specimens, but there was discordance. The RMA assay detected significantly more human metapneumovirus (HMPV) and respiratory syncytial virus (RSV), while RT-rtPCR detected significantly more influenza A. We speculated that primer differences accounted for these discrepancies and redesigned the primers and probes for influenza A in the RMA assay, and for HMPV and RSV in the RT-rtPCR assay. The tests were then repeated and again compared. The new primers led to improved detection of HMPV and RSV by RT-rtPCR assay, but the RMA assay remained similar in terms of influenza detection.ConclusionsGiven the absence of a gold standard, clinical and research laboratories should regularly correlate the results of molecular assays with other PCR based assays, other laboratories, and with standard virologic methods to ensure consistency and accuracy.

New Human Rhinovirus Species and Their Significance in Asthma Exacerbation and Airway Remodeling

Asthma is the most common chronic disease of childhood, affecting 10% to 15% of all children. Several different stimuli including allergens, tobacco smoke, certain drugs, and viral or bacterial infections are known to exacerbate asthma symptoms. Among these triggers, viruses are frequent inducers of asthma exacerbations, with human rhinoviruses being the most common in children and adults. This article describes the different species of this virus and their roles as major triggers of asthma exacerbations.