Burden of respiratory syncytial virus, human metapneumovirus and influenza virus infections in Japanese adults in the Hospitalized Acute Respiratory Tract Infection study.

BACKGROUND: Respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and influenza virus are responsible for acute respiratory tract infections (ARTIs) in adults. We assessed the clinical burden of RSV, hMPV and influenza virus infection among Japanese adults hospitalized with ARTIs. METHODS: The Hospitalized Acute Respiratory Tract Infection (HARTI) study was a multinational, prospective cohort study in adults with ARTIs across the 2017-2019 epidemic seasons. Enrolment in Japan began in Sept 2018 and ran until Oct 2019. The clinical diagnosis of ARTI and the decision to hospitalize the patient were made according to local standard of care practices. Viral testing was performed by reverse transcription polymerase chain reaction. RESULTS: Of the 173 adults hospitalized with ARTI during this period at the Japan sites, 7 (4.0%), 9 (5.2%), and 11 (6.4%) were positive for influenza virus, RSV, and hMPV, respectively. RSV season was observed from Oct 2018 to Jan 2019, followed by influenza from Dec 2018 to Apr 2019. hMPV was detected across both the RSV and influenza seasons. Two patients with RSV and 1 patient with hMPV required ICU admission whereas none with influenza. Use of antibiotics, bronchodilators and inhaled corticosteroids was high amongst patients with RSV and hMPV at 1, 2, and 3 months' post-discharge compared with patients with influenza, with few exceptions. CONCLUSION: These findings highlight the need for a high degree of clinical suspicion for RSV and hMPV infection in adults hospitalized with ARTIs.

Assessment of Illness Severity in Adults Hospitalized With Acute Respiratory Tract Infection due to Influenza, Respiratory Syncytial Virus, or Human Metapneumovirus.

BACKGROUND: Influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) are common respiratory viruses causing similar symptoms. Optimal tools to assess illness severity for these viruses have not been defined. Using the Hospitalized Acute Respiratory Tract Infection (HARTI) study data, we report symptom severity by clinician-rated clinical severity scores (CSS) in adults with influenza, RSV, or hMPV and correlations between CSS and patient-reported outcomes (PROs). METHODS: HARTI was a global epidemiologic study in adults hospitalized with acute respiratory tract infections. Patients were assessed at enrollment within 24 h of admission with CSS and twice during hospitalization with CSS, Respiratory Infection Intensity and Impact Questionnaire™ (RiiQ™), and EQ-5D-5L. Data were summarized descriptively, stratified by pathogen and baseline and hospitalization characteristics. Domain (general, upper respiratory, and lower respiratory) and sign/symptom subscores are presented for CSS; sign/symptom subscores are presented for RiiQ™ results. RESULTS: Data from 635 patients with influenza, 248 with RSV, and 107 with hMPV were included. At enrollment, total CSS and general and lower respiratory signs/symptoms (LRS) scores were higher for RSV and hMPV than influenza. Between-pathogen differences were greatest for LRS scores. Dyspnea, rales/rhonchi, wheezing, and shortness of breath scores trended higher for RSV and hMPV than influenza. RiiQ™ scores for cough, fatigue, and short of breath were strongly correlated with corresponding clinician-rated symptoms. CONCLUSIONS: These findings support the use of PROs (e.g., the RiiQ™) correlating with clinician assessments to gauge patient well-being and aid patient management by accurately assessing respiratory illness severity due to RSV, hMPV, or influenza.

Comparative assessment of reported symptoms of influenza, respiratory syncytial virus, and human metapneumovirus infection during hospitalization and post-discharge assessed by Respiratory Intensity and Impact Questionnaire.

BACKGROUND: The hospitalized acute respiratory tract infection (HARTI) study used the Respiratory Intensity and Impact Questionnaire (RiiQ™) Symptom Scale, derived from FluiiQ™, to assess and compare the burden of respiratory infection symptoms for patients with influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) infection, with or without core risk factors (CRF) (age ≥65; chronic heart, renal, obstructive pulmonary disease; asthma). METHODS: This was a prospective cohort study in adult patients hospitalized with acute respiratory tract infection (40 centers, 12 countries) during two consecutive influenza/RSV/hMPV seasons (2017-2019). The RiiQ™ Symptom Scale and EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) were assessed by interview at two timepoints during hospitalization and at 1, 2, and 3 months post-discharge. RESULTS: Mean lower respiratory tract (LRT) symptom scores were higher for RSV and hMPV participants compared to influenza at 48 h after enrollment/early discharge (p = 0.001) and 3 months post-discharge (p = 0.007). This was driven by LRT symptoms, including shortness of breath (SOB) (p < 0.01) and wheezing (p < 0.01) during hospitalization, and SOB (p < 0.05) and cough (p < 0.05) post-discharge. Participants with CRF reported more moderate-to-severe SOB (p < 0.05) and wheezing (p < 0.05) compared to CRF(-) participants post-discharge. EQ-5D-5L scores were moderately associated with RiiQ™ LRT and systemic symptoms domains. CONCLUSIONS: Results from the HARTI study suggest that in the study population, LRT symptoms were more severe for RSV and hMPV groups and for patients with CRF. RiiQ™ Symptom Scale scores shows a moderate association with EQ-5D-5L indicating that the RiiQ™ may provide useful insights and offer advantages over other measures for use in interventional RSV adult clinical studies.

Occurrence and disease burden of respiratory syncytial virus and other respiratory pathogens in adults aged ≥65 years in community: A prospective cohort study in Japan.

BACKGROUND: The frequency and clinical profile of respiratory syncytial virus (RSV)-acute respiratory disease (ARD) in older adults in Japan has not been well-characterized. METHODS: This was a multicenter prospective observational cohort study to evaluate the occurrence rate of ARD in 1000 older adult participants (≥65 years) for 52 weeks during the 2019 to 2020 season. A multiplex polymerase chain reaction panel was used for pathogen detection in nasopharyngeal swab from participants diagnosed with ARD. Symptoms and impact of ARD was assessed using the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™). The study was registered at UMIN (https://www.umin.ac.jp/ctr/): UMIN000037891. RESULTS: RSV-ARD was detected in 24/1000 (2.4%) participants and RSV-lower respiratory tract disease in 8/1000 (0.8%) participants. The median duration of RSV-ARD was 18 days. All 24 participants had utilized the medical services of outpatient visits and only 1 (4.2%) participant was hospitalized for RSV-ARD. The most common viruses other than RSV that caused ARD (detected in >10 participants) were human rhinovirus/enterovirus, parainfluenza 3, coronavirus OC43, human metapneumovirus, and influenza A/H1. The most frequent symptoms of RSV-ARD were cough, sore throat, nasal congestion, and expectoration. CONCLUSIONS: RSV was reported as a major pathogen for respiratory infections in older adults in Japan.

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

BACKGROUND: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. METHODS: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. FINDINGS: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. INTERPRETATION: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

A review on epidemiology and impact of human metapneumovirus infections in children using TIAB search strategy on PubMed and PubMed Central articles.

Acute respiratory tract infections (ARTI) contribute to morbidity and mortality in children globally. Viruses including human metapneumovirus (hMPV) account for most ARTIs. The virus causes upper and lower respiratory tract infections mostly in young children and contributes to hospitalization of individuals with asthma,chronic obstructive pulmonary diseases and cancer. Moreover, hMPV pauses a considerable socio-economic impact creating a substantial disease burden wherever it has been studied, although hMPV testing is relatively new in many countries. We aimed to comprehensively analyze the epidemiological aspects including prevalence, disease burden and seasonality of hMPV infections in children in the world. We acquired published data extracted from PubMed and PubMed Central articles using the title and abstract (TIAB)search strategy for the major key words on hMPV infections from 9/54 African, 11/35 American, 20/50 Asian, 2/14 Australian/Oceanian and 20/51 European countries. According to the findings of this review, the prevalence of hMPV infection ranges from 1.1 to 86% in children of less than 5 years of age globally. Presence of many hMPV genotypes (A1, A2, B1, B2) and sub-genotypes (A2a, A2b, A2c, B2a, B2b) suggests a rapid evolution of the virus with limited influence by time and geography. hMPV infection mostly affects children between 2 to 5 years of age. The virus is active throughout the year in the tropics and epidemics occur during the winter and spring in temperate climates, contributing to a substantial disease burden globally.

Human metapneumovirus in paediatric intensive care unit (PICU) admissions in the United Kingdom (UK) 2006-2014.

BACKGROUND: Human metapneumovirus (HMPV) is a pneumovirus known to cause respiratory disease in children. It was identified as a pathogen in 2001 and its healthcare burden and associated costs are not fully understood. OBJECTIVES: This study aimed to assess the clinical characteristics of children with HMPV infection admitted to paediatric intensive care units (PICUs) across the United Kingdom (UK) over a nine-year period and to estimate the associated costs of care. STUDY DESIGN: Data were collected from the UK paediatric intensive care audit network (PICANet) and costs calculated using the National Health Service (NHS) reference costing scheme. RESULTS: There were 114 admissions in which HMPV was detected. The number of admissions associated with a code of HMPV rose steadily over the study period (three in 2006 to 28 in 2014) and showed significant seasonal variability, with the peak season being from November to May. Children required varying levels of intensive care support from minimal to complex support including invasive ventilation, inotropes, renal replacement therapy and extracorporeal membrane oxygenation (ECMO). HMPV was associated with five deaths during the study period. The associated costs of PICU admissions were estimated to be between £2,256,823 and £3,997,823 over the study period, with estimated annual costs rising over the study period due to increasing HMPV admissions. CONCLUSIONS: HMPV is associated with a significant healthcare burden and associated cost of care in PICUs in the UK.

Burden of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Asthmatic Children.

BACKGROUND: Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory illness in children. Clinical burden of each infection on the respiratory distress in asthmatic patients remains unclear. The purpose of the study was to clarify the effect of these infections on the severity of asthmatic children in the seasonal outbreaks. METHODS: A total of 1,217 pediatric inpatients with hMPV (n = 114) or RSV (n = 1,103) infection in Yamaguchi prefecture, Japan, between 2011 and 2014 were enrolled. Bronchial asthma was defined as having more than 3 episodes of wheezing illness over 1 year of age. Infection was determined by the positive antigen test for each virus in the nasal specimens. RESULTS: The number of patients peaked at age 12-15 months in hMPV infection and at age 0-3 months in RSV infection. The proportion of hypoxic patients (40-50%) did not differ at any age between hMPV-infected and RSV-infected children. In the analysis of date from > 1 year old patients with hypoxia, hMPV-infection group was older (P = 0.036), and more frequently had history of asthma (P = 0.015) or abnormal chest roentgenogram (P < 0.001) than RSV-infection group. Multivariate analysis indicated that the hypoxia-associated factors were history of asthma in both hMPV (odds ratio [OR]: 15.8; P < 0.001) and RSV infections (OR, 2.2; P = 0.005), higher body temperature in hMPV infection (OR, 2.2; P = 0.009), and younger age in RSV infection (OR, 1.4; P = 0.004). CONCLUSIONS: Outbreaks of hMPV, rather than, RSV infection may have a greater impact on the development of hypoxic respiratory illness in asthmatic children.

Evaluation of 793/B-like and Mass-like vaccine strain kinetics in experimental and field conditions by real-time RT-PCR quantification.

Infectious bronchitis virus (IBV) is a great economic burden both for productive losses and costs of the control strategies. Many different vaccination protocols are applied in the same region and even in consecutive cycles on the same farm in order to find the perfect balance between costs and benefits. In Northern Italy, the usual second vaccination is more and more often moved up to the chick's first d of life. The second strain administration together with the common Mass priming by spray at the hatchery allows saving money and time and reducing animal stress. The present work compared the different vaccine strains (Mass-like or B48, and 1/96) kinetics both in field conditions and in a 21-day-long experimental trial in broilers, monitoring the viral replication by upper respiratory tract swabbing and vaccine specific real time reverse transcription PCR (RT-PCR) quantification. In both field and experimental conditions, titers for all the vaccines showed an increasing trend in the first 2 wk and then a decrease, though still remaining detectable during the whole monitored period. IBV field strain and avian Metapneumovirus (aMPV) presence also was also investigated by RT-PCR and sequencing, and by multiplex real-time RT-PCR, respectively, revealing a consistency in the pathogen introduction timing at around 30 d, in correspondence with the vaccine titer's main decrease. These findings suggest the need for an accurate knowledge of live vaccine kinetics, whose replication can compete with the other pathogen one, providing additional protection to be added to what is conferred by the adaptive immune response.

The Burden of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Norwegian Children.

Background: The burden of severe human metapneumovirus (HMPV) respiratory tract infections (RTIs) in European children has not been clarified. We assessed HMPV in Norwegian children and compared hospitalization rates for HMPV and respiratory syncytial virus (RSV). Methods: We prospectively enrolled children (<16 years old) hospitalized with RTI and asymptomatic controls (2006-2015). Nasopharyngeal aspirate samples were analyzed with polymerase chain reaction (PCR) tests for HMPV, RSV, and 17 other pathogens. We genotyped HMPV-positive samples and assessed shedding time in 32 HMPV-infected children. Results: In children with RTI, HMPV was detected in 7.3% (267 of 3650) and RSV in 28.7% (1048 of 3650). Among controls, 2.1% (7 of 339) had low HMPV levels detected by PCR, but all were culture negative. HMPV primarily occurred from January to April and in regular epidemics. At least 2 HMPV subtypes occurred each season. The average annual hospitalization rates in children <5 years old with lower RTI were 1.9/1000 (HMPV) and 10.4/1000 (RSV). Among children with RTI, the median HMPV shedding time by PCR was 13 days (range, 6-28 days), but all were culture negative (noninfectious) after 13 days. Conclusions: HMPV appears in epidemics in Norwegian children, with a hospitalization rate 5 times lower than RSV. Low levels of HMPV are rarely detected in healthy children.

Incidence, Morbidity, and Costs of Human Metapneumovirus Infection in Hospitalized Children.

BACKGROUND: Human metapneumovirus (HMPV) causes acute respiratory tract infections in infants and children. We sought to measure the clinical and economic burden of HMPV infection in hospitalized children. METHODS: We conducted a retrospective cohort study from 2007 to 2013 at Primary Children's Hospital in Salt Lake City, Utah. Children <18 years of age with laboratory-confirmed HMPV infection were included. Demographic, clinical, and financial data were abstracted from the electronic medical record. RESULTS: During the study period, 815 children were hospitalized with laboratory-confirmed HMPV infection: 16% <6 months, 50% 6-23 months, 23% 2-4 years, and 11% 5-17 years of age. A complex chronic condition was identified in 453 (56%) children hospitalized with HMPV infection; this proportion increased with increasing age (P < .001). There was marked variation in annual HMPV hospitalization rates, ranging from 9 of 100 000 person-years in 2012-2013 to 79 of 100 000 in 2009-2010. Hospitalization rates were highest among children <2 years (200 of 100 000 person-years) and lowest among children 5-17 years of age (5 of 100 000). Of hospitalized children, 18% were treated in the intensive care unit and 6% required mechanical ventilation. The median length of stay was 2.8 days (interquartile range [IQR], 1.8-4.6) and did not vary by age. The median total hospital cost per patient was $5513 (IQR, $3850-$9946) with significantly higher costs for patients with chronic medical conditions (P < .001). CONCLUSIONS: Human metapneumovirus infection results in a large number of hospitalizations with substantial morbidity, resource utilization, and costs. The development of a safe and effective vaccine could reduce the clinical and economic burden of HMPV.

Incidence of viral respiratory infections in a prospective cohort of outpatient and hospitalized children aged ≤5 years and its associated cost in Buenos Aires, Argentina.

BACKGROUND: Although information about the incidence of viral respiratory illnesses and their associated cost can help health officials explore the value of interventions, data are limited from middle-income countries. METHODS: During 2008-2010, we conducted a prospective cohort study and followed ~1,800 Argentinian children aged ≤5 years to identify those children who were hospitalized or who sought care at an emergency room with any acute respiratory infection sign or symptom (e.g., rhinorrhea, cough, wheezing, tachypnea, retractions, or cyanosis). Respiratory samples were obtained for respiratory syncytial virus, influenza, parainfluenza, adenovirus, and metapneumovirus testing by immunofluorescence and for rhinovirus by real-time reverse transcription polymerase chain reaction. RESULTS: The incidence of respiratory syncytial virus (24/1000 children-years), human metapneumovirus (8/1000 children-years), and influenza (8/1000 children-years) illnesses was highest among hospitalized children aged <6 months and decreased among older children. In contrast, the incidence of rhinovirus was highest (12/1000 children-years) among those aged 6-23 months. In the emergency room, the incidence of rhinovirus was 459; respiratory syncytial virus 352; influenza 185; parainfluenza 177; metapneumovirus 130; and adenovirus 73/1,000 children-years. The total cost of hospitalization was a median of US$529 (Interquartile range, US$362-789). CONCLUSIONS: Our findings indicate that respiratory viruses, in particular rhinovirus, respiratory syncytial virus, metapneumovirus, and influenza may be associated with severe illness causing substantial economic burden.

A sensitive, reproducible, and economic real-time reverse transcription PCR detecting avian metapneumovirus subtypes A and B.

Use of real-time PCR is increasing in the diagnosis of infectious disease due to its sensitivity, specificity, and speed of detection. These characteristics make it particularly suited for the diagnosis of viral infections, like avian metapneumovirus (AMPV), for which effective control benefits from continuously updated knowledge of the epidemiological situation. Other real-time reverse transcription (RT)-PCRs have been published based on highly specific fluorescent dye-labeled probes, but they have high initial cost, complex validation, and a marked susceptibility to the genetic variability of their target sequence. With this in mind, we developed and validated a SYBR Green I-based quantitative RT-PCR for the detection of the two most prevalent AMPV subtypes (i.e., subtypes A and B). The assay demonstrated an analytical sensitivity comparable with that of a previously published real-time RT-PCR and the ability to detect RNA equivalent to approximately 0.5 infectious doses for both A and B subtypes. The high efficiency and linearity between viral titer and crossing point displayed for both subtypes make it suited for viral quantification. Optimization of reaction conditions and the implementation of melting curve analysis guaranteed the high specificity of the assay. The stable melting temperature difference between the two subtypes indicated the possibility of subtyping through melting temperature analysis. These characteristics make our assay a sensitive, specific, and rapid tool, enabling contemporaneous detection, quantification, and discrimination of AMPV subtype A and B.

Generation and biological assessment of recombinant avian metapneumovirus subgroup C (aMPV-C) viruses containing different length of the G gene.

Genetic variation in length of the G gene among different avian metapneumovirus subgroup C (aMPV-C) isolates has been reported. However, its biological significance in virus replication, pathogenicity and immunity is unknown. In this study, we developed a reverse genetics system for aMPV-C and generated two Colorado (CO) strain-based recombinant viruses containing either the full-length G gene derived from a Canadian goose isolate or a C-terminally truncated G gene of the CO strain. The truncated short G (sG) gene encoded 252 amino acids (aa), which is 333 aa shorter than the full-length G (585 aa). The biological properties of these two recombinant G variants were assessed in Vero cells and in specific-pathogen-free (SPF) turkeys. In Vero cells, the short G variant displayed a similar level of growth dynamics and virus titers as the parental aMPV-CO strain, whereas the full-length G variant replicated less efficiently than the sG variant during the first 72 h post-infection. Both of the G variants induced typical cytopathic effects (CPE) that were indistinguishable from those seen with the parental aMPV-CO infection. In SPF turkeys, both of the G variants were attenuated and caused little or no disease signs, but the full-length G variant appeared to grow more readily in tracheal tissue than the sG variant during the first 5 days post-infection. Both G variants were immunogenic and induced a slightly different level of antibody response. These results demonstrated that the large portion (333 aa) of the extracellular domain of the viral attachment protein is not essential for virus viability in vitro and in vivo, but may play a role in enhancing virus attachment specificity and immunity in a natural host.

Incidence, molecular epidemiology and clinical presentations of human metapneumovirus; assessment of its importance as a diagnostic screening target.

BACKGROUND: Human metapneumovirus (HMPV) is a recently discovered human paramyxovirus associated with a spectrum of respiratory symptoms from the common cold to pneumonia and bronchiolitis. OBJECTIVES: To assess the clinical significance and epidemiology of HMPV, standardized comparison of frequencies of infection, age profiles and disease associations were made with other respiratory viruses in Scotland. STUDY DESIGN: 7091 respiratory samples collected in Scotland between 1 July 2006 and 30 June 2008 from 4282 individuals were screened by multiplex RT-PCR for respiratory syncytial virus (HRSV), adenovirus (AdV), parainfluenza viruses 1-3 (PIV-1, -2 and -3), influenza A and B and by nested RT-PCR for HMPV. RESULTS: HMPV was the fifth most prevalent virus (2.0% of samples), found predominantly in young children in winter months. In the 2006-2007 respiratory season, 70% of HMPV isolates were genotype A, but a switch to predominantly type B infections occurred next winter. For samples with information on clinical presentations, 26% of HMPV infections were from subjects with lower respiratory tract presentations, lower than recorded for HRSV, but similar to adenovirus, parainfluenza viruses and influenza viruses A and B. Around 13% of HMPV infections were associated with upper respiratory tract symptoms or disease, comparable with other respiratory virus infections. CONCLUSIONS: Numerically and through its association with respiratory disease, HMPV represents a diagnostically significant target that should be included in PCR-based routine screening of respiratory samples. Understanding the biological basis of observed rapid turnover of HMPV variants, including the observed HMPV genotype change between respiratory seasons requires further longitudinal studies.

Evolutionary dynamics of human and avian metapneumoviruses.

Human (HMPV) and avian (AMPV) metapneumoviruses are closely related viruses that cause respiratory tract illnesses in humans and birds, respectively. Although HMPV was first discovered in 2001, retrospective studies have shown that HMPV has been circulating in humans for at least 50 years. AMPV was first isolated in the 1970s, and can be classified into four subgroups, A-D. AMPV subgroup C is more closely related to HMPV than to any other AMPV subgroup, suggesting that HMPV has emerged from AMPV-C upon zoonosis. Presently, at least four genetic lineages of HMPV circulate in human populations - A1, A2, B1 and B2 - of which lineages A and B are antigenically distinct. We used a Bayesian Markov Chain Monte Carlo (MCMC) framework to determine the evolutionary and epidemiological dynamics of HMPV and AMPV-C. The rates of nucleotide substitution, relative genetic diversity and time to the most recent common ancestor (TMRCA) were estimated using large sets of sequences of the nucleoprotein, the fusion protein and attachment protein genes. The sampled genetic diversity of HMPV was found to have arisen within the past 119-133 years, with consistent results across all three genes, while the TMRCA for HMPV and AMPV-C was estimated to have existed around 200 years ago. The relative genetic diversity observed in the four HMPV lineages was low, most likely reflecting continual population bottlenecks, with only limited evidence for positive selection.

Rates of hospitalisation for influenza, respiratory syncytial virus and human metapneumovirus among infants and young children.

To inform the development of a national influenza immunisation programme and the potential role of antiviral drugs in young children, we studied 613 children aged 71 months or younger who attended Leicester Childrens' Hospital during winter 2001-2002. During periods of respiratory syncytial virus (RSV), influenza, and human metapneumovirus activity, an estimated 12.2% (95% CI: 11.4-13.1), 7.1% (6.3-7.9), and 2.5% (2.1-2.9), respectively, of all medical cases assessed in the hospital were associated with these infections. The respective rates of hospital assessments for RSV, influenza, and human metapneumovirus (HMPV) were 1042 (95% CI: 967-1021), 394 (348-443), and 223 (189-262) per 100,000 children, and for admissions were 517 (465-574), 144 (117-175), and 126 (101-156) per 100,000. Few children with influenza had a prior risk factor. Children with influenza were admitted a median of 4 days after onset of illness and none was coded at discharge as influenza. We conclude that antivirals have little role in the hospital management of children with influenza. Our data provide health economists with information to evaluate the place of universal immunisation of young children against influenza. Hospitalisation rates decreased markedly with referral age, so vaccine would need to be given in early infancy for maximum benefit.

Detection of severe human metapneumovirus infection by real-time polymerase chain reaction and histopathological assessment.

BACKGROUND: Infections with common respiratory tract viruses can cause high mortality, especially in immunocompromised hosts, but the impact of human metapneumovirus (hMPV) in this setting was previously unknown. METHODS: We evaluated consecutive bronchoalveolar lavage and bronchial wash fluid samples from 688 patients--72% were immunocompromised and were predominantly lung transplant recipients--for hMPV by use of quantitative real-time polymerase chain reaction (PCR), and positive results were correlated with clinical outcome and results of viral cultures, in situ hybridization, and lung histopathological assessment. RESULTS: Six cases of hMPV infection were identified, and they had a similar frequency and occurred in a similar age range as other paramyxoviral infections. Four of 6 infections occurred in immunocompromised patients. Infection was confirmed by in situ hybridization for the viral nucleocapsid gene. Histopathological assessment of lung tissue samples showed acute and organizing injury, and smudge cell formation was distinct from findings in infections with other paramyxoviruses. Each patient with high titers of hMPV exhibited a complicated clinical course requiring prolonged hospitalization. CONCLUSIONS: Our results provide in situ evidence of hMPV infection in humans and suggest that hMPV is a cause of clinically severe lower respiratory tract infection that can be detected during bronchoscopy by use of real-time PCR and routine histopathological assessment.