Our findings show that among children who were younger than 5 years of age, the annual rate of hospitalization associated with HMPV was 1 per 1000 children, which is the same as the rates of hospitalization associated with influenza virus, at 1 per 1000, and parainfluenza virus types 1, 2, and 3 combined, at 1 per 1000,22,23
but lower than the rate for RSV, at 3 per 1000.20
Thus, the potential inpatient burden of disease associated with HMPV is similar to that associated with other common respiratory viruses (Table 1 in the Supplementary Appendix
). Extrapolation of these rates on the basis of U.S. Census data suggests that approximately 20,000 hospitalizations associated with HMPV infection occur annually among children less than 5 years of age.
The rates of outpatient visits associated with detectable HMPV infection were 55 per 1000 clinic visits and 13 per 1000 ED visits, which were lower than the rates of RSV infection among out-patients (80 per 1000 clinic visits and 28 per 1000 visits, according to the NVSN).20
However, the rates of outpatient visits associated with HMPV infection were similar to those for influenza during the 2002–2003 season (50 per 1000 clinic visits and 6 per 1000 ED visits) but were lower than the rates for influenza during the 2003–2004 season (95 per 1000 clinic visits and 27 per 1000 ED visits)22
(Table 2 in the Supplementary Appendix
). The average annual rates of HMPV-associated outpatient visits were approximately 20, 50, and 80 times as high as the rates of HMPV-associated hospitalization among children less than 6 months, 6 to 23 months, and 24 to 59 months of age, respectively. Extrapolation of these rates to the U.S. population suggests that 1 million outpatient clinic visits and 263,000 ED visits may be associated with HMPV infection annually among U.S. children less than 5 years of age.
The rates of HMPV-associated clinic and ED visits were highest among children 6 to 11 months of age, in contrast to rates for HMPV-associated hospitalization, which were highest among children less than 6 months old. Furthermore, the rate of HMPV-associated outpatient visits among older children remained similar to the rate among young infants. This pattern is in contrast to that for RSV infection, for which outpatient rates decreased markedly after 1 year of age.20
Thus, HMPV, like influenza virus, may cause clinically significant disease throughout early childhood.22
During most of the study period, there were no commercially available diagnostic tests for HMPV, and the virus is difficult to culture. Thus, few children would have received a diagnosis of HMPV infection in the clinical setting. Rapid diagnostic tools for HMPV detection would identify infection in these children.
In this cohort, 40% of children hospitalized with HMPV infection had underlying high-risk conditions, including premature birth and asthma, whereas only 22% of outpatient children with HMPV infection had a high-risk condition. Other reports have also identified a substantial number of children with high-risk conditions who were hospitalized with HMPV infection.3,4,7,8,30–32
Conversely, nearly two thirds of inpatients and three quarters of outpatients with HMPV infection were otherwise healthy. These data suggest that all children are at risk for HMPV infection requiring medical attention, which provides important information to guide future prevention efforts, including vaccine development.
The clinical features of HMPV infection are similar to those of infections due to other respiratory viruses.9,11,25,30
However, hospitalized children with detectable HMPV infection were more likely than those without HMPV infection to require supplemental oxygen and had longer ICU stays, possibly reflecting underlying conditions that predisposed them to more severe disease. There were no deaths associated with HMPV infection, RSV infection, or influenza in the study cohort.20,25
Nonetheless, the data show that HMPV is capable of causing severe disease, and fatal HMPV infections have been reported.1,7,12,13,16,18,33–41
Furthermore, children with HMPV infection were more likely than those without the infection to undergo chest radiography, possibly owing to the absence of a specific viral diagnosis.
A small minority of children with HMPV had other viruses detected with the use of an RT-PCR assay. HMPV was detected in a few asymptomatic children, although at significantly lower viral loads than those in symptomatic children; higher viral loads have been correlated with more severe illness.42–46
Although parents of control children were asked about concurrent respiratory symptoms, it is possible that some children had an acute respiratory illness before enrollment and were still shedding virus; conversely, these children may have been in the early stage of HMPV infection, and illness that subsequently developed was not recorded. HMPV shedding can last from 1 to 2 weeks after acute illness.11,30,31,47
As with many pathogens, caution is warranted in attributing illness to HMPV when the virus is detected, since detection does not prove causation. However, other studies have shown that HMPV is rarely detected in asymptomatic children.11,27,28
Furthermore, virus challenge with HMPV causes acute respiratory illness in nonhuman primates and small-animal species that is clinically, histologically, and virologically similar to the disease in humans.48–55
Although the peak of HMPV detection varied from year to year, the prevalence of HMPV overlapped with the circulation of other common respiratory viruses. This finding underscores the strength of a multiyear study in delineating the epidemiologic features of HMPV. As with RSV and influenza virus, regular community-based, year-round surveillance is needed to define the onset and duration of HMPV activity. The similarity of clinical symptoms associated with different viruses strongly supports the need for specific molecular diagnostic methods for precise viral identification.
Our study has some limitations. First, our data can only reflect association, and in the absence of a specific intervention, we cannot infer that HMPV was the causal factor in the illnesses we observed. Second, our study population may not be representative of the entire U.S. population or that of other locations, despite the large number of patients enrolled over 6 years at three sites. Third, children were enrolled only from November through May, and some eligible children were excluded owing to missing samples or protocol deviations. Thus, we may have underestimated or overestimated the overall burden of HMPV infection. Fourth, institutional differences in medical practice may have affected hospitalization rates, but we used strict inclusion criteria and prospective data collection. Finally, children with neutropenia who were receiving treatment for cancer were excluded, although HMPV can cause severe and fatal disease in such children.7,12,18,35,56,57
Additional studies in special populations are needed to capture the complete burden of HMPV disease.
In conclusion, HMPV is frequently associated with acute respiratory illness in young children that requires medical attention, and HMPV infection represents a substantial health care burden among both inpatients and outpatients.