Clinical characteristics

The first description of hMPV in children with lower RTI has been reported by a Dutch group that identified the virus in respiratory secretions [1]. Clinical symptoms were similar to those caused by RSV, ranging from upper RTI, severe bronchiolitis and pneumonia during the winter season. All 28 children observed were < 5 years of age, and 46% were < 1 year old. Asymptomatic carriage seems to be rare in children; no hMPV was detected in 400 infants without respiratory symptoms.

The prevalence and clinical symptoms of hMPV-infected patients, identified by RT-PCR in respiratory samples obtained from patients in a university hospital, indicated that the prevalence and clinical severity due to hMPV infections are slightly lower than those of RSV infections during the winter season [32]. Most of the hMPV-positive patients were children < 2 years old without any underlying illnesses. hMPV was found significantly less frequently than RSV in children < 2 months old. Of the 31 hMPV-posi-tive children < 2 years old, only 4 (31%) were < 2 months old, whereas 43 (35%) of the 122 hRSV-positive children < 2 years old were also < 2 months old. Others have found that the mean age of patients infected with hMPV was slightly lower than that compared to RSV [39]. Of the hMPV-posi-tive patients who were > 5 years old, most had other diseases (e.g., cystic fibrosis, leukemia, and non-Hodgkin lymphoma) or had recently received bone marrow or kidney transplantation, indicating an association with immunosuppression. Two severely immunocompromised patients died due to progressive respiratory failure with hMPV as the sole pathogen detected [69]. In studies involving young and elderly adults, hMPV caused more severe disease in fragile elderly than in healthy elderly or young adults [4, 41]. Clinical symptoms in children < 10 years of age (n = 238) due to hMPV infection include cough (82%), rhinitis (67%), fever (72%), respiratory distress (71%), wheezing (59%), and retractions (54%) [29, 30-32, 37, 39, 69]. Specific clinical syndromes caused by hMPV seem to differ from that caused by other respiratory viruses. Williams et al. [39] tested respiratory specimens over a 25-year period in the US from previously healthy children. Infection due to hMPV was more likely to be associated with bronchiolitis and less likely to be associated with croup than infection due to (para)influenza virus. hMPV infection was less likely to be associated with pneumonia than was infection with RSV or influenza virus. Various studies show frequent involvement (16-24%) of hMPV in acute bronchiolitis in infants, a percentage only second to RSV [18, 33, 70]. hMPV is associated with a substantial number of URTI episodes in otherwise healthy outpatient children with clinical illnesses similar to those associated with other common viruses, including frequent acute otitis media [16].

Studies examining the role of hMPV with respect to exacerbations of asthma have yielded conflicting results [35, 39, 57]. Two studies in adult patients with chronic obstructive pulmonary disease (COPD) showed that hMPV could be detected in 2.5% of the hospitalized COPD patients with an acute exacerbation [14, 71], while no hMPV was detected in stable COPD patients. Although there is no doubt that some patients with asthmatic exacerbations have hMPV infection, whether or not the virus is associated more frequently than other respiratory viruses with these exacerbations is not yet clear. Remarkably, a history of asthma or a family member with asthma was more often associated with hMPV (16% and 67%, respectively) than with RSV (0% and 30%, respectively) [9].

The similar seasonality and susceptible population shared by several respiratory viral infections will result in prevalent co-infection of hMPV with other respiratory viruses. This might lead to an underestimation of the percentage of hMPV-positive samples identified in studies in which only samples negative for other respiratory viruses were tested (see also Tabs 1 and 2). Co-infection rates of 5-10% with one or more respiratory viruses have been demonstrated in several studies searching for the causative pathogen of RTI. Because the epidemic seasonality for RSV coincides with that for hMPV, the potential exists for RSV/hMPV co-infections. Several studies have identified cases of lower RTI in which evidence for the presence of both RSV and hMPV has been detected [23, 33, 39, 72]. Dual infection with RSV and hMPV was more frequent in infants with severe disease (i.e., those who needed supplementary oxygen) and even more frequent in infants with severe disease admitted to the intensive care unit for mechanical ventilation [26, 72]. Foulongne et al. [24] showed that another respiratory virus was detected in 32% of hMPV-positive samples obtained from children < 5 years of age with RTI, and all but one of these co-infections involved RSV. Duration of hospitalization and requirement for supplemental oxygen was significantly higher in hMPV/RSV co-infected children. Greensill et al. [73] collected non-bronchoscopic bronchoalveolar samples from 30 infants < 48 weeks of age ventilated with RSV bronchiolitis diagnosed by antigen testing. Detection of hMPV was performed by RT-PCR of the M, F, and N genes. In 16 of the 24 infants with a positive RT-PCR for RSV in the bronchoalveolar lavage sample, genomic hMPV was also detectable. This high rate of co-infection raises the possibility that co-infection with RSV and hMPV is a determinant of disease severity. These results were confirmed by others studying the association between severe bronchiolitis and dual infection by RSV and hMPV in children < 2 years of age who were admitted to the hospital. Co-infection with both viruses conferred a tenfold increase in relative risk of admission to a pediatric intensive care unit for mechanical ventilation. A high case incidence (52%) of hMPV infection has been described in association with hospital admission of patients with severe acute respiratory syndrome in Hong Kong [43].

In contrast, others found a similar rate of bronchopneumonia in infants infected with hMPV alone as in dual infections [33]. Wilkesmann et al. [23] did not find a lower illness severity when comparing hMPV-infected children with matched RSV-infected children without hMPV co-infections. On the other hand, the seasonal distribution of hHMP and RSV may differ in specific geographic areas as demonstrated in studies from Argentina and Hong Kong where co-infections were not or infrequently observed [9, 37]. The peak of hMPV in these countries becomes prevalent in late winter and early spring. It is likely that by the development of more sensitive detection methods, dual or mixed infections will be increasingly recognized, and do not necessarily result in more severe infection. A positive RT-PCR test result does not differentiate between active infection and prolonged shedding after a recent acute infection that has been terminated.

It is currently not known whether hMPV infection leads to an increased susceptibility to secondary bacterial infections. The absence of sensitive tools to diagnose bacterial pneumonia has been an obstacle to defining the role of bacterial co-infection in children with virus-associated pneumonia. In a hypothesis-generating study involving a cohort of children randomized to receive the 9-valent pneumococcal vaccine or placebo, children were tested for the presence of hMPV by a nested RT-PCR when admitted to the hospital with a lower RTI. In both HIV-uninfected and HIV-infected children the incidence of hMPV-associated lower RTI was reduced by 46%, and the incidence of clinical pneumonia was reduced by 58% [74]. These data, combined with comparable finding for other respiratory viruses [75], suggest that respiratory viral infections as caused by hMPV predispose to pneumococcal co-infection and that bacterial-viral co-infections are important in the pathogenesis of virus-associated pneumonia in children.

The socioeconomic impact of hMPV infection on children and their households is not well known. It is reported that household contacts of hMPV-infected children, like influenza-infected children, fell ill significantly more frequently, required more medical visits, received more anti-pyretic prescriptions, and were also absent more frequently from work or school, than those of RSV-infected children [76]. These findings suggest that hMPV infection in children considerably affects their families.

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