Spectrum of Disease Associated with Human Metapneumovirus Infection in Children

Abstract & Commentary

Synopsis: Human metapneumovirus was the likely cause of 12% of all lower respiratory tract illnesses among a population of 2009 children studied from 1976 to 2001 presenting with acute respiratory symptoms. Clinical manifestations of metapneumovirus infection were bronchiolitis (59%), croup (18%), pneumonia (8%), and exacerbation of asthma (14%).

Source: Williams JV, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med. 2004;350:443-450.

From 1976 to 2001, 2009 children were enrolled in a prospective study of viral respiratory tract infections. Children with symptomatic lower respiratory tract infection were diagnosed with bronchiolitis, pneumonia, or laryngotracheobronchitis (croup) based on diagnostic clinical signs and radiographic findings. Nasal-wash specimens for virus cultures were obtained at 687 of 1127 visits (61%) of children diagnosed with lower respiratory tract infections. These cultures identified a viral etiology in 279 specimens, including from 103 children with respiratory syncytial virus (including 5 coinfected with another virus), 58 with parainfluenza virus, 32 with influenza virus, 28 with adenovirus, and 50 with enterovirus, rhinovirus, poliovirus, herpes simplex virus, or rotavirus. Of the remaining 408 specimens from 321 children who were previously negative by virus culture, 248 had available samples for RNA extraction for an RT-PCR assay of a highly conserved region of human metapneumovirus. Of these 248 specimens, 49 (20%) were positive for human metapneumovirus by RT-PCR. Nasal-wash specimens from 96 children diagnosed with lower respiratory tract infection who had positive cultures for another virus were tested for human metapneumovirus by RT-PCR. Of these, 4 (4%) were positive, indicating a coinfection rate of 4%. There was no apparent clinical difference in children with human metapneumovirus alone compared to those with coinfections. An additional 86 nasal-wash specimens from children without respiratory symptoms were also tested for human metapneumovirus by RT-PCR, and only 1 was positive.

For human metapneumovirus infection, the male:female ratio was 1.8:1, and the mean age of infection was 11.6 months, with a median of 6.5 months and a range of 1.5-50 months. Infection was predominantly during infancy, with 25% of infections among children younger than 6 months of age and 49% among children 6-12 months of age. The peak period of infection was March, with 78% of illnesses occurring between December and April. However, infections occurred throughout the year with less seasonal prominence than for respiratory syncytial virus. The annual proportion of lower respiratory tract infections attributable to human metapneumovirus varied from 0% to 31% during this 25-year period.

Of the 49 children with human metapneumovirus infection, the clinical diagnosis was bronchiolitis in 29 (59%), croup in 9 (18%), pneumonia in 4 (8%), and exacerbation of asthma in 7 (14%). Acute otitis medial was diagnosed in 18 (37%). Compared to respiratory syncytial virus infection, human metapneumovirus was associated with comparable rates of fever but less frequent rales (8% vs 24%; P = .03) and wheezing (52% vs 69%; P = .04), at rates similar to parainfluenza virus, influenza virus, and adenovirus infections. Fever was more common with influenza virus (87% vs 52%; P = .001). Chest radiographs were obtained in 14 children, with abnormalities in 7 (50%) consisting of diffuse perihilar infiltrates. Only 1 child (2%), who was 36 months of age, was hospitalized, with a diagnosis of exacerbation of asthma triggered by a viral respiratory tract infection.

Comment by Hal B. Jenson, MD, FAAP, Chair, Department of Pediatrics, Director, Center for Pediatric Research, Eastern Virginia Medical School and Children’s Hospital of the King’s Daughters, Norfolk, VA and Associate Editor of Infectious Disease Alert.

Human metapneumovirus was first reported by researchers in the Netherlands who isolated an agent from 28 respiratory specimens that induced cytopathic effects on cultured cells.1 Sequence and phylogenetic analysis revealed that this new pathogen was likely a paramyxovirus and most closely related to an avian pneumovirus. This agent was determined to be the first human pathogen member of the genus Metapneumovirus, in the Paramyxoviridae family, and was called human metapneumovirus. The closest related human virus is respiratory syncytial virus, of the genus Pneumovirus and also in the Paramyxoviridae family. This report confirms previous reports of the frequent incidence of human metapneumovirus infection and, more importantly, defines the spectrum of clinical manifestations of human metapneumovirus disease in children.

Human metapneumovirus infection occurs primarily among infants and very young children and causes both upper and lower respiratory tract symptoms. The spectrum of disease—primarily causing bronchiolitis but also causing croup, pneumonia, and associated with exacerbations of asthma—is very similar to that observed with RSV, including the predisposition to secondary otitis media. Both viruses have peak incidence in late winter months.

This study also demonstrates that human metapneumovirus has been prevalent in the United States for at least the past 25 years. In this cohort of children diagnosed with lower respiratory tract infection, human metapneumovirus accounted for 20% of all cases of lower respiratory tract infections without a prior virologic diagnosis, with an overall prevalence of 12%. The prevalence of human metapneumovirus was second only to respiratory syncytial virus (15%) and was higher than parainfluenza virus (10%), influenza virus (5%), and adenovirus (4%). One caveat is that these other viruses were confirmed by culture, and the PCR method for human metapneumovirus was likely more sensitive than was culture for the other viruses.

Human metapneumovirus is an important respiratory tract pathogen in healthy infants and young children but has escaped identification because it is difficult to detect by virus culture. It is an important cause of bronchiolitis and pneumonia in infants and very young children. It is most similar in seasonality, with late winter epidemics, and clinical manifestations to respiratory syncytial virus, but it appears less severe and with variation in severity from year to year. The frequency and severity of human metapneumovirus disease in adults and the elderly remain to be determined.

Reference

1. Van Den Hoogen BG, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7:719-724.