Human metapneumovirus infection is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to that of respiratory syncytial virus.

WHAT'S KNOWN ON THIS SUBJECT: Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. Most estimates of RSV hospitalization rates are imprecise, having been calculated by using retrospective discharge diagnosis data and stratified age groups no narrower than 6 to 12 months.WHAT THIS STUDY ADDS: Prospective, population-based surveillance data for infants hospitalized with laboratoryconfirmed RSV infection were combined with birth certificate information to yield more precise age-specific hospitalization rates. These data should help determine priorities for the use of existing and future RSV prophylaxis strategies. abstract BACKGROUND: Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. However, estimates of the RSV hospitalization burden have varied, and precision has been limited by the use of age strata grouped in blocks of 6 to $12 months. METHODS:We analyzed data from a 5-year, prospective, population-based surveillance for young children who were hospitalized with laboratoryconfirmed (reverse-transcriptase polymerase chain reaction) RSV acute respiratory illness (ARI) during October through March 2000-2005. The total population at risk was stratified by month of age by birth certificate information to yield hospitalization rates.RESULTS: There were 559 (26%) RSV-infected children among the 2149 enrolled children hospitalized with ARI (85% of all eligible children with ARI). The average RSV hospitalization rate was 5.2 per 1000 children ,24 months old. The highest age-specific rate was in infants 1 month old (25.9 per 1000 children). Infants #2 months of age, who comprised 44% of RSV-hospitalized children, had a hospitalization rate of 17.9 per 1000 children. Most children (79%) were previously healthy. Very preterm infants (,30 weeks' gestation) accounted for only 3% of RSV cases but had RSV hospitalization rates 3 times that of term infants.CONCLUSIONS: Young infants, especially those who were 1 month old, were at greatest risk of RSV hospitalization. Four-fifths of RSVhospitalized infants were previously healthy. To substantially reduce the burden of RSV hospitalizations, effective general preventive strategies will be required for all young infants, not just those with risk factors. Pediatrics 2013;132:e341-e348 AUTHORS:

BACKGROUND The inpatient and outpatient burden of human metapneumovirus (HMPV) infection among young children has not been well established. METHODS We conducted prospective, population-based surveillance for acute respiratory illness or fever among inpatient and outpatient children less than 5 years of age in three U.S. counties from 2003 through 2009. Clinical and demographic data were obtained from parents and medical records, HMPV was detected by means of a reverse-transcriptase polymerase-chain-reaction assay, and population-based rates of hospitalization and estimated rates of outpatient visits associated with HMPV infection were determined. RESULTS HMPV was detected in 200 of 3490 hospitalized children (6%), 222 of 3257 children in outpatient clinics (7%), 224 of 3001 children in the emergency department (7%), and 10 of 770 asymptomatic controls (1%). Overall annual rates of hospitalization associated with HMPV infection were 1 per 1000 children less than 5 years of age, 3 per 1000 infants less than 6 months of age, and 2 per 1000 children 6 to 11 months of age. Children hospitalized with HMPV infection, as compared with those hospitalized without HMPV infection, were older and more likely to receive a diagnosis of pneumonia or asthma, to require supplemental oxygen, and to have a longer stay in the intensive care unit. The estimated annual burden of outpatient visits associated with HMPV infection was 55 clinic visits and 13 emergency department visits per 1000 children. The majority of HMPV-positive inpatient and outpatient children had no underlying medical conditions, although premature birth and asthma were more frequent among hospitalized children with HMPV infection than among those without HMPV infection. CONCLUSIONS HMPV infection is associated with a substantial burden of hospitalizations and outpatient visits among children throughout the first 5 years of life, especially during the first year. Most children with HMPV infection were previously healthy. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health.)

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.

Viruses are leading causes of severe acute lower respiratory infections (LRIs). These infections evoke incomplete immunity, as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid pulmonary CD8 + cytotoxic T lymphocyte (T CD8 ) functional impairment via programmed death-1/ programmed death ligand-1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated T CD8 impairment occurred acutely in mice following infection with human metapneumovirus or influenza virus. Viral antigen was sufficient for PD-1 upregulation, but induction of PD-L1 was required for impairment. During secondary viral infection or epitope-only challenge, memory T CD8 rapidly reexpressed PD-1 and exhibited severe functional impairment. Inhibition of PD-1 signaling using monoclonal antibody blockade prevented T CD8 impairment, reduced viral titers during primary infection, and enhanced protection of immunized mice against challenge infection. Additionally, PD-1 and PD-L1 were upregulated in the lungs of patients with 2009 H1N1 influenza virus, respiratory syncytial virus, or parainfluenza virus infection. These results indicate that PD-1 mediates T CD8 functional impairment during acute viral infection and may contribute to recurrent viral LRIs. Therefore, the PD-1/PD-L1 pathway may represent a therapeutic target in the treatment of respiratory viruses.

In adults aged ≥ 50 years, hospitalization rates for RSV and HMPV were similar to those associated with influenza.

hMPV was detected in a substantial number of children with URIs and concomitant AOM.

Airway mucus is a hallmark of respiratory syncytial virus (RSV) lower respiratory tract illness. Laboratory RSV strains differentially induce airway mucus production in mice. Here, we tested the hypothesis that RSV strains differ in pathogenesis by screening six low-passage RSV clinical isolates for mucogenicity and virulence in BALB/cJ mice. The RSV clinical isolates induced variable disease severity, lung interleukin-13 (IL-13) levels, and gob-5 levels in BALB/cJ mice. We chose two of these clinical isolates for further study. Infection of BALB/cJ mice with RSV A2001/2-20 (2-20) resulted in greater disease severity, higher lung IL-13 levels, and higher lung gob-5 levels than infection with RSV strains A2, line 19, Long, and A2001/3-12 (3-12). Like the line 19 RSV strain, the 2-20 clinical isolate induced airway mucin expression in BALB/cJ mice. The 2-20 and 3-12 RSV clinical isolates had higher lung viral loads than laboratory RSV strains at 1 day postinfection (p.i.). This increased viral load correlated with higher viral antigen levels in the bronchiolar epithelium and greater histopathologic changes at 1 day p.i. The A2 RSV strain had the highest peak viral load at day 4 p.i. RSV 2-20 infection caused epithelial desquamation, bronchiolitis, airway hyperresponsiveness, and increased breathing effort in BALB/cJ mice. We found that RSV clinical isolates induce variable pathogenesis in mice, and we established a mouse model of clinical isolate strain-dependent RSV pathogenesis that recapitulates key features of RSV disease.Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and viral pneumonia in children. Each year in the United States, RSV causes lower respiratory tract illness (LRI) in 20 to 30% of infants and leads to the hospitalization of approximately 1% of infants at a cost of $300 to $400 million (19,21,27). The incidence and disease severity of RSV can vary from year to year (47). Dominant circulating RSV strains are generally replaced each year, likely by a process involving immune selection (5,6,53,54). RSV strain differences may contribute to year-to-year and/or patient-topatient variations in clinical severity.In BALB/cJ mice, laboratory RSV strains (A2, Long, and line 19) differ in their ability to cause pulmonary interleukin-13 (IL-13) and mucin expression (34, 41). We are interested in RSV-induced mucin expression in mice because mucus overabundance contributes to airway obstruction in severe RSV disease in children (2,33,44,56). IL-13 is a cytokine linked to mucus production (71). The line 19 RSV strain induces lung IL-13 and airway mucin expression in BALB/cJ mice, whereas the A2 and Long RSV strains do not (34, 41). However, the in vitro passage histories of RSV strains A2, Long, and line 19 are not defined and involve many serial passages. Thus, it is possible that mutations in these RSV laboratory strains determine pathogenesis phenotypes in the mouse model. RSV clinical isolates have not been studied extensively in vivo, and the role of RSV strain differences in...