Acta Pædiatrica ISSN 0803-5253
COMMENTARY
Rhinovirus bronchiolitis: to be or not to be? Matti Korppi ([email protected]) Tampere Centre for Child Health Research, Tampere University and University Hospital, Tampere, Finland
Correspondence Professor Matti Korppi, MD, PhD, Tampere Centre for Child Health Research, Tampere University and University Hospital, FM-3 building, 33014 Tampere, Finland. Tel: +358-50-3186316 | Fax: +358-3-2254109 | Email: [email protected] Received 17 June 2014; accepted 2 July 2014 DOI:10.1111/apa.12737
Bronchiolitis is a viral lower respiratory tract infection characterised by inflammation and obstruction of the small airways. Respiratory syncytial virus (RSV) is the most common causative agent, followed by parainfluenza viruses, adenoviruses and the recently discovered metapneumovirus. Birth cohort studies have reported that the incidence of bronchiolitis is 18–32% during the first year of life, and 1– 3% of infants need hospitalisation for bronchiolitis, with the majority being admitted before 6 months of age (1). In European countries, bronchiolitis is usually defined as the first virus-induced wheezing episode in infants under the age of 12 months, but in the USA, and in most previous studies, the upper age limit has been 24 months (2). The risk of severe bronchiolitis is highest in infants under the age of 3 months, who are less likely to exhibit wheezing than older infants. From a clinical point of view, the optimal upper age limit for bronchiolitis is likely to be 6 months (3). This age tends to separate a homogeneous group of young infants who often need to be hospitalised, due to a severe illness that puts them at risk of hypoxia and insufficient fluid intake, from the more heterogeneous group of wheezing older infants who are usually treated at home. Diagnostic tests for respiratory viral infections have markedly improved over the last 20 years. The development of polymerase chain reaction (PCR) technique has enabled us to identify previously unknown viruses such as the metapneumovirus and human bocavirus, and to re-evaluate the role of known viruses such as rhinoviruses. Rhinoviruses comprise more than 100 serologically differing subgroups with no major common antigens, which results in two important consequences: first, the development of
workable serological tests has not been successful and second, children face many repeated rhinovirus infections during the first years of life (1). PCR-based methods have played a key role in improving rhinovirus diagnostics, which further has changed our concepts on the aetiology, predisposing factors and long-term outcome of early-life wheezing (1). Despite this progress, the question of whether rhinoviruses are real causative agents of bronchiolitis in young infants remains unresolved. In this issue of the journal, Midulla et al. (4) discuss their findings on a 3-year follow-up of infants hospitalised in Italy for bronchiolitis under the age of 12 months. As previously published, 195 viruses were detected by PCR in nasal wash samples from 174 (56%) of the 313 bronchiolitis patients (5). Rhinoviruses were identified in 24 cases (14% of viruspositive, 7.7% of all patients). The parents were contacted by phone on three occasions after their child’s admission for bronchiolitis and the response rates were 85% at 12 months, 77% at 24 months and 73% at 36 months. Wheezing during the first and second postbronchiolitis years was a significant predictor of wheezing during the third postbronchiolitis year (4). In adjusted analyses, blood eosinophils >0.4 9 10E9/L (odds ratio 7.7) and rhinovirus identification during bronchiolitis (odds ratio 3.1), were the only independently significant risk factors for postbronchiolitis wheezing during the third postbronchiolitis year (4). The prevalence of rhinovirus-associated wheezing increases steadily with age and the cut-off age of the dominance between RSV and rhinovirus has been about 12 months in hospital studies (1). Recent multicentre studies that focused on 1620 American (6) and 206 Finnish
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 997–999
997
Commentary
Commentary
(7) infants hospitalised for RSV and/or rhinovirus-positive bronchiolitis under the age of 12 months, showed that 6.3– 8.1% were rhinovirus-positive as an only viral finding. In the Finnish study (7), 11.2% were rhinovirus-positive when co-infections with viruses other than RSV were included, and 14.0% when all co-infections including also those with RSV were included. The susceptibility to rhinovirus-induced wheezing in infancy seems to be linked to a predisposition to other conditions, such as atopy and eosinophilic activity (1,8). Thus, there may be a subgroup of infants under 12-months old with early-life respiratory allergy who are prone to wheeze during rhinovirus infections. As allergy is often subclinical at that early age, a positive rhinovirus finding during bronchiolitis may be more useful in predicting the risk of subsequent wheezing or later asthma than different allergy studies that are often undertaken in wheezing infants. However, although rhinovirus detection as a marker of asthma risk in the first episode of infant wheezing is specific, it only concerns a small group of infants. Children who present with repeated wheezing are at an increased risk of asthma, or even have asthma, irrespective of viral findings. The next theoretical calculations are based on the hypothesis that all infants under the age of 12 months who are hospitalised for rhinovirus-positive bronchiolitis are potential asthma patients in the future. First we assume that 3% of infants are hospitalised annually for bronchiolitis (1), and the rhinovirus is likely to be identified as the only virus in 7.5% of them (4–7). If the prevalence of childhood asthma is 5%, we can estimate that 4.5% of future patients with childhood asthma can be picked up by detecting rhinoviruses in infants hospitalised for bronchiolitis. If we reduce the assumption on the incidence of bronchiolitis hospitalisations to 1%, and increase the assumption on the prevalence of childhood asthma to 10%, only 0.75% of future patients with childhood asthma can be picked up by positive rhinovirus PCR in infants hospitalised for bronchiolitis. Birth cohort and postbronchiolitis studies offer different perspectives for the same problem. In the birth cohort study from Wisconsin, USA, 285 newborns whose parents had respiratory allergies were followed up prospectively for 1 year, 275 for 3 years and 259 for 6 years (9,10). All respiratory infections until the age of 12 months were studied at an outpatient clinic, where the infants were examined by a doctor and respiratory samples were taken for virus identification. In addition to sampling when the patients were symptomatic, samples were routinely collected and tests were carried out every third month when they were healthy. Wheezing associated with rhinovirus infection during the first year of life increased the risk of subsequent wheezing during the third year of life to 6.6-fold (9) and the risk of asthma at 6 years of age to 2.7-fold (10). However, only 2.5% of infants were hospitalised for bronchiolitis under the age of 12 months, including just one rhinovirus-positive case (0.4% of all cases). In the Finnish postbronchiolitis study, the asthma risk was 10-fold at the median age of 7.2 years after hospitalisation for
998
rhinovirus infection associated wheezing when compared to RSV infection associated wheezing at
COMMENTARY
Rhinovirus bronchiolitis: to be or not to be? Matti Korppi ([email protected]) Tampere Centre for Child Health Research, Tampere University and University Hospital, Tampere, Finland
Correspondence Professor Matti Korppi, MD, PhD, Tampere Centre for Child Health Research, Tampere University and University Hospital, FM-3 building, 33014 Tampere, Finland. Tel: +358-50-3186316 | Fax: +358-3-2254109 | Email: [email protected] Received 17 June 2014; accepted 2 July 2014 DOI:10.1111/apa.12737
Bronchiolitis is a viral lower respiratory tract infection characterised by inflammation and obstruction of the small airways. Respiratory syncytial virus (RSV) is the most common causative agent, followed by parainfluenza viruses, adenoviruses and the recently discovered metapneumovirus. Birth cohort studies have reported that the incidence of bronchiolitis is 18–32% during the first year of life, and 1– 3% of infants need hospitalisation for bronchiolitis, with the majority being admitted before 6 months of age (1). In European countries, bronchiolitis is usually defined as the first virus-induced wheezing episode in infants under the age of 12 months, but in the USA, and in most previous studies, the upper age limit has been 24 months (2). The risk of severe bronchiolitis is highest in infants under the age of 3 months, who are less likely to exhibit wheezing than older infants. From a clinical point of view, the optimal upper age limit for bronchiolitis is likely to be 6 months (3). This age tends to separate a homogeneous group of young infants who often need to be hospitalised, due to a severe illness that puts them at risk of hypoxia and insufficient fluid intake, from the more heterogeneous group of wheezing older infants who are usually treated at home. Diagnostic tests for respiratory viral infections have markedly improved over the last 20 years. The development of polymerase chain reaction (PCR) technique has enabled us to identify previously unknown viruses such as the metapneumovirus and human bocavirus, and to re-evaluate the role of known viruses such as rhinoviruses. Rhinoviruses comprise more than 100 serologically differing subgroups with no major common antigens, which results in two important consequences: first, the development of
workable serological tests has not been successful and second, children face many repeated rhinovirus infections during the first years of life (1). PCR-based methods have played a key role in improving rhinovirus diagnostics, which further has changed our concepts on the aetiology, predisposing factors and long-term outcome of early-life wheezing (1). Despite this progress, the question of whether rhinoviruses are real causative agents of bronchiolitis in young infants remains unresolved. In this issue of the journal, Midulla et al. (4) discuss their findings on a 3-year follow-up of infants hospitalised in Italy for bronchiolitis under the age of 12 months. As previously published, 195 viruses were detected by PCR in nasal wash samples from 174 (56%) of the 313 bronchiolitis patients (5). Rhinoviruses were identified in 24 cases (14% of viruspositive, 7.7% of all patients). The parents were contacted by phone on three occasions after their child’s admission for bronchiolitis and the response rates were 85% at 12 months, 77% at 24 months and 73% at 36 months. Wheezing during the first and second postbronchiolitis years was a significant predictor of wheezing during the third postbronchiolitis year (4). In adjusted analyses, blood eosinophils >0.4 9 10E9/L (odds ratio 7.7) and rhinovirus identification during bronchiolitis (odds ratio 3.1), were the only independently significant risk factors for postbronchiolitis wheezing during the third postbronchiolitis year (4). The prevalence of rhinovirus-associated wheezing increases steadily with age and the cut-off age of the dominance between RSV and rhinovirus has been about 12 months in hospital studies (1). Recent multicentre studies that focused on 1620 American (6) and 206 Finnish
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 997–999
997
Commentary
Commentary
(7) infants hospitalised for RSV and/or rhinovirus-positive bronchiolitis under the age of 12 months, showed that 6.3– 8.1% were rhinovirus-positive as an only viral finding. In the Finnish study (7), 11.2% were rhinovirus-positive when co-infections with viruses other than RSV were included, and 14.0% when all co-infections including also those with RSV were included. The susceptibility to rhinovirus-induced wheezing in infancy seems to be linked to a predisposition to other conditions, such as atopy and eosinophilic activity (1,8). Thus, there may be a subgroup of infants under 12-months old with early-life respiratory allergy who are prone to wheeze during rhinovirus infections. As allergy is often subclinical at that early age, a positive rhinovirus finding during bronchiolitis may be more useful in predicting the risk of subsequent wheezing or later asthma than different allergy studies that are often undertaken in wheezing infants. However, although rhinovirus detection as a marker of asthma risk in the first episode of infant wheezing is specific, it only concerns a small group of infants. Children who present with repeated wheezing are at an increased risk of asthma, or even have asthma, irrespective of viral findings. The next theoretical calculations are based on the hypothesis that all infants under the age of 12 months who are hospitalised for rhinovirus-positive bronchiolitis are potential asthma patients in the future. First we assume that 3% of infants are hospitalised annually for bronchiolitis (1), and the rhinovirus is likely to be identified as the only virus in 7.5% of them (4–7). If the prevalence of childhood asthma is 5%, we can estimate that 4.5% of future patients with childhood asthma can be picked up by detecting rhinoviruses in infants hospitalised for bronchiolitis. If we reduce the assumption on the incidence of bronchiolitis hospitalisations to 1%, and increase the assumption on the prevalence of childhood asthma to 10%, only 0.75% of future patients with childhood asthma can be picked up by positive rhinovirus PCR in infants hospitalised for bronchiolitis. Birth cohort and postbronchiolitis studies offer different perspectives for the same problem. In the birth cohort study from Wisconsin, USA, 285 newborns whose parents had respiratory allergies were followed up prospectively for 1 year, 275 for 3 years and 259 for 6 years (9,10). All respiratory infections until the age of 12 months were studied at an outpatient clinic, where the infants were examined by a doctor and respiratory samples were taken for virus identification. In addition to sampling when the patients were symptomatic, samples were routinely collected and tests were carried out every third month when they were healthy. Wheezing associated with rhinovirus infection during the first year of life increased the risk of subsequent wheezing during the third year of life to 6.6-fold (9) and the risk of asthma at 6 years of age to 2.7-fold (10). However, only 2.5% of infants were hospitalised for bronchiolitis under the age of 12 months, including just one rhinovirus-positive case (0.4% of all cases). In the Finnish postbronchiolitis study, the asthma risk was 10-fold at the median age of 7.2 years after hospitalisation for
998
rhinovirus infection associated wheezing when compared to RSV infection associated wheezing at
