Metapneumovirus and acute wheezing in children.

A new respiratory virus, human metapneumovirus, was recently identified. We detected this virus by PCR in ten (8%) of 132 consecutive children admitted to Turku Hospital, Finland, for acute expiratory wheezing (median age 7 months, range 4-25). The mean duration of hospital stay was 2.5 days (SD 1.6) and mean duration of respiratory symptoms was 19 days (8). The white blood cell count, C-reactive protein, and regulated upon activation, normal T-cell-expressed and T-cell-secreted (RANTES) concentrations in nasal secretion remained low, whereas interleukin 8 concentrations in nasal secretion were high. Human metapneumovirus is a clinically important causative agent of acute wheezing in young children.

Investigators from the Netherlands and North America have identified an earlier unknown virus from the Paramyxoviridae family, human metapneumovirus. Identification of this virus was based on virological data, sequence homology, and gene constellation. Clinically and cytopathologically, infection with human metapneumovirus resembles that of respiratory syncytial virus, ranging from mild upper respiratory tract disease to severe bronchiolitis and pneumonia in children. Results of a serological survey showed that human metapneumovirus usually infects young children; all 80 children in the survey in the Netherlands at the age of 5 years were seropositive for the virus. We investigated the frequency of human metapneumovirus in children admitted to the paediatric department of Turku University Hospital, Finland for acute expiratory airway obstruction.

Between Sept 1, 2001, and May 31, 2001, 132 consecutive children participated in the continuing study of the efficacy of systemic glucocorticoids in acute expiratory wheezing in the Department of Paediatrics, Turku University Hospital, Finland. We included children if they were aged 3 months to 16 years, had been admitted for acute expiratory wheezing, and if their parents had provided written informed consent. Children were excluded if they had a chronic disease other than asthma or allergy, had taken systemic glucocorticoids 4 weeks or less before the start of the study, or had severe wheezing and treatment in an intensive care unit. The median age of the children was 2·0 years (range 4·0 months to 13·5 years). 25 children were diagnosed with bronchiolitis, 59 with wheezy bronchitis, and 48 with acute asthma. The study protocol was approved by the ethics committee of Turku University Central Hospital.

On admission, we obtained nasopharyngeal aspirates and assessed them for presence of human metapneumovirus with a reverse transcriptase PCR assay using primers in the L gene that detect both genotypes of the virus. The primers were tested for specificity against members of the respective paramyxovirus genera and the assay detected 0·01 tissue culture infective dose 50/mL virus. We cultured the aspirates and assessed the presence of antigens of influenza A, influenza B, adenovirus, respiratory synctial virus, and parainfluenza types 1, 2, and 3, and did PCR for coronavirus, rhinovirus, and enterovirus. Primer sequences and experimental methods are available from the authors. Symptoms were recorded by the parents using a home diary for 2 weeks after discharge.

We identified a potential causative viral agent in 116 (88%) of the 132 children; 31 (27%) had rhinovirus, 26 (22%) had enterovirus, 19 (16%) had non-typable picornavirus, 16 (14%) had respiratory syncytial virus, and ten (9%) had human metapneumovirus. Seven of these ten children had human metapneumovirus alone; the other three children also had other respiratory viruses. Human metapneumovirus was detected in children only from from January to April, 2001. The median age of the children with human metapneumovirus was 7 months (range 4–25). Five children had bronchiolitis, four wheezy bronchitis, and one newly detected asthma. No child had previously used glucocorticoids.

On admission, in children with human metapneumovirus, cough had lasted for a mean of 9 days (SD 10), rhinitis for 4 days (5), expiratory wheezing for 3 days (2), and fever for 3 days (2). Two of the seven children with human metapneumovirus alone were diagnosed with acute otitis media. The mean axillary temperature was 37·8·C (1·0) and the mean oxygen saturation was 96% (2). Children had a mean of 9·5×109 white blood cells/L (3·0×109) and a mean serum C-reactive protein concentration of 9 mg/L (11). The mean interleukin 8 concentration in nasopharyngeal aspirates obtained from six children was 480 ng/L (360) and the mean concentration of regulated by activation, normal T-cell expressed and secreted (RANTES) was 50 ng/L (31). All patients were given nebulised salbutamol. The patients were randomly allocated to receive 2 mg/kg oral prednisolone per day for 3 days or placebo. The study code has not yet been opened. The mean duration of hospital stay was 69 h (45). After hospital stay, the cough had lasted for a mean of 7 days (4), dyspnoea for 6 days (5), and low fever for 0·4 days (0·9). One of the seven patients was readmitted to hospital within 2 weeks because of recurrent breathing difficulties.

In our study, the clinical diagnosis and age of the patients was closely similar to those seen in studies of infection with respiratory syncytial virus.1, 4 However, human metapneumovirus arose at a different time from respiratory syncytial virus infections. Human metapneumovirus was identified from the middle of winter to spring-a time when a limited spring epidemic of respiratory syncytial virus had just started in Finland. From January to April, 2001, we identified human metapneumovirus in ten (32%) of the 31 children with wheezing.

The chemokine profile of interleukin 8 (mainly a chemotactic factor for neutrophils) and RANTES (chemotactic factor for eosinophils) in nasal secretions was different to that reported in infections with respiratory syncytial virus. Patients with respiratory syncytial virus had high concentrations of RANTES and varying concentrations of interleukin 8, whereas in our study, children with human metapneumovirus had low concentrations of RANTES and high concentrations of interleukin 8. The cytokine concentrations and blood samples were not confounded by use of prednisolone because the samples were taken before treatment. Clinically, the efficacy of systemic glucocorticoids in bronchiolitis remains unknown.

Our results suggest that human metapneumovirus is a causative agent of acute wheezing in young children. During the study period, this virus was identified in childen at a time when other common causative agents, rhinovirus and respiratory syncytial virus, were not epidemic. Although the white blood cell counts and concentrations of C-reactive protein remained low, as usually found in viral infection, the inflammatory response to human metapneumovirus was different from that seen in respiratory syncytial virus infection.