We used molecular studies and culture to test the hypothesis that human metapneumovirus is a major cause of lower respiratory tract infection in children. We evaluated prospectively acquired respiratory samples from a longitudinal study of children conducted over a period of 25 years. Human metapneumovirus was present in 20 percent of all cases of lower respiratory tract infection without a prior virologic diagnosis. Extrapolation of these results suggests that 81 human metapneumovirus infections would be expected among the entire group of 408 cases of previously negative lower respiratory tract infection, leading to an overall prevalence in this cohort of 687 children with lower respiratory tract infection of 12 percent. The prevalence of other viruses in this cohort with lower respiratory tract infection was 15 percent for RSV, 10 percent for parainfluenza virus, 5 percent for influenzavirus, and 4 percent for adenovirus. One must be cautious about making direct comparisons of the prevalence of this virus with that of other viruses, which were detected by cell-culture methods. Previous reports suggested that PCR-based diagnostic techniques increase the sensitivity of viral detection.16,17
Nonetheless, although the population-based incidence and prevalence cannot be determined from these data, our findings suggest that human metapneumovirus causes lower respiratory tract infection in healthy children at a relatively high frequency. Other reports have noted human metapneumovirus in 4 to 16 percent of specimens obtained from patients with acute respiratory tract infection and submitted to diagnostic virology laboratories.4,18–20
Three additional reports on acute respiratory tract infection in adult outpatients noted rates of human metapneumovirus infection of 2 to 7 percent.7,21,22
The lower rates found in adults may reflect decreased levels of viral shedding or methodologic differences among the reports.
The demographic features associated with human metapneumovirus infection suggested the classic characteristics of a viral respiratory tract infection of infancy. Male sex was associated with an increased risk of lower respiratory tract disease, as it is for other respiratory viruses. Three quarters of all lower respiratory tract infections caused by human metapneumovirus occurred in the first year of life. Disease due to human metapneumovirus occurred in late winter epidemics that coincided with the latter half of the RSV season. In contrast to a recent report,23
we did not find evidence of increased severity of disease in children who were coinfected with human metapneumovirus and other viruses, though the number of these children was small.
We also found human metapneumovirus in 15 percent of patients with upper respiratory tract infections. In contrast, human metapneumovirus was detected in only one healthy child, although some of these samples were collected during the summer months, when the virus appears to be less prevalent. Osterhaus and Fouchier22
found only one positive specimen among 600 asymptomatic adults and children who were tested. In previous studies at our clinic, adenovirus was isolated from only one of 174 asymptomatic children.9
Similarly, viruses were not isolated on day 0 from 68 children in studies of RSV vaccine.24
The clinical features of lower respiratory tract infection with human metapneumovirus were similar to those of infections caused by other paramyxoviruses. The statistical association of human metapneumovirus infection with asthma was intriguing in the light of recent conflicting reports regarding a possible association between this infection and asthma.20,25
However, the biologic significance of this association is unknown, and asthma is a difficult clinical diagnosis to make in young children.
The limitations of this study include the fact that the use of frozen specimens for RT-PCR and viral culture of human metapneumovirus may have diminished the yield. Although contamination is a concern with the use of highly sensitive techniques such as PCR, we used stringent criteria and sequenced all PCR products, thus reducing the risk of false positive results, but potentially eliminating true positive results that did not meet our criteria. These factors may have led us to underestimate the frequency of respiratory tract infections caused by human metapneumovirus.
An association between the presence of a virus and symptoms of respiratory tract disease does not necessarily establish causation. Nevertheless, the clinical, demographic, radiographic, and genetic evidence suggests that there is a strong association between human metapneumovirus and lower respiratory tract infection in otherwise healthy children and that human metapneumovirus is a major cause of bronchiolitis and croup in the pediatric population. Lower respiratory tract infections occurred predominantly in the first year of life, during the late winter months. The hospitalization rate was similar to that for RSV infection, and otitis media was a frequent complication. Our data, collected prospectively over a period of 25 years, demonstrate the seasonal occurrence of human metapneumovirus infection and define the spectrum of clinical disease caused by this novel human pathogen.