Viral infections in infancy
RSV is the most common respiratory pathogen in early childhood, with most children having had a RSV infection by 2 years of age. The majority of children suffer only a coryzal illness (common cold symptoms) requiring no medical intervention, but others develop bronchiolitis or RSV pneumonia requiring hospital admission and even intensive care. There are a number of risk factors for severe RSV infection (table 1) and therefore for increased respiratory illness at follow-up. Numerous studies have demonstrated that RSV infection in otherwise healthy infants born at term is associated with long-term respiratory sequelae. However, the effect appears to decrease with increasing age: in one cohort, although significantly more children who had had RSV LRTI wheezed up to 5 years of age compared to controls, there was no significant difference in children aged 5–10 years. Other studies report an increase in asthma in adults following RSV infection in infancy. However, the results of studies assessing bronchial hyperreactivity or allergic sensitisation following RSV infection in children born at term are conflicting. In prematurely born children who had BPD, hospitalisation due to RSV infection in the first 2 years after birth was associated with increased healthcare utilisation and associated costs up to 7 years of age. Lung function abnormalities at follow-up following RSV LRTI have been described in both term and prematurely born children.
The fact that 30–50% of children with viral-induced wheezing in infancy go on to develop asthma suggests that viral respiratory infections cause airway damage, promoting airway remodelling, leading to asthma. There is, however, evidence to suggest that infants who have symptomatic RSV LRTIs may have pre-existing diminished lung function, particularly small-airway abnormalities. In one study, however, the results were not significant and virology results were only available for the two infants who were hospitalised. Follow-up of the cohort highlighted that lung function level at 11 years of age was similar to the pre-infection level, suggesting that the infection had not had an adverse effect. In prematurely born infants, a higher resistance of the respiratory system at 36 weeks’ post-menstrual age has been associated with more wheeze at follow-up following RSV LRTI and, in a larger cohort, with a greater requirement for RSV hospitalisation. Some single nucleotide polymorphisms (SNPs) have been associated with an increased risk of severe RSV infection as indicated by a need for hospitalisation. In addition, SNPs in genes coding for interleukin (IL)-8, IL-19, IL-20, IL-13, mannose binding lectin, interferon (IFN)-γ and RANTES (regulated upon activation, normal T-cell expressed, and secreted) have been associated with wheeze following RSV LRTI in term-born infants.
There is evidence that other respiratory viral infections may be associated with chronic respiratory morbidity in childhood. The chronic lung damage that can result from adenovirus infection in young children has frequently been reported. Asthma has been reported to be significantly more common in 5-year-old children who had been admitted to hospital with either human metapneumovirus (hMPV) or RSV bronchiolitis in infancy. Prematurely born infants with either a hMPV LRTI or a RSV LRTI have been found to be more likely to cough and wheeze at follow-up and have lung function abnormalities, particularly a higher airway resistance.
It may be that the impact of other viruses, particularly rhinovirus (RV), is even greater than that of RSV. Among children at increased risk of developing allergies and asthma, the most significant risk factor for the development of pre-school childhood asthma was the occurrence of a symptomatic RV illness during infancy. In another study, out of 14 respiratory viruses, RV was most likely to be associated with recurrent wheezing at 12 months in infants who had been hospitalised for their first episode of bronchiolitis.
A number of hypotheses have been put forward to explain the association of RV wheezing illnesses and asthma development. These include that predisposition by allergic sensitisation reduces IFN responses in infants with asthma. As a consequence, there is increased viral replication and impaired barrier function due to smoke exposure, pollution and/or virus infection, which again leads to enhanced viral replication, greater illness severity and airway damage.
A ‘double hit hypothesis’ for atopy and viral infection has been proposed as, in the Perth Birth Cohort, there was an increase in the odds ratio of developing asthma at age 6 years in patients with a greater number of viral respiratory infections in the first year after birth who were atopic. In that cohort, RV was the most common pathogen associated with an acute respiratory infection in the first year after birth. Prospective follow-up of another cohort demonstrated that allergic sensitisation preceded RV wheezing but the converse was not true. Hence, the researchers suggested that the timing and plausible mechanisms by which allergic sensitisation led to more severe RV illness supported a causal role for allergic sensitisation in that developmental pathway.
It has been suggested that the development of asthma may be related to immature immune responses to respiratory viruses and that the timing of the viral respiratory infection is an important predictor of asthma. In the Tennessee Database study, infants born 4 months prior to the winter virus peak were 30% more likely to have asthma than infants born 12 months before the winter virus peak. Viral infections, RV in particular, can activate a number of pro-inflammatory and airway remodelling pathways that might have deleterious effects on the rapidly growing airways of young children. There may also be a functional predisposition to RV-associated wheeze, as an increased risk of wheeze has been reported in infants with a higher pre-infection resistance of the respiratory system.