The current report describes a pilot study using novel imaging techniques in children genetically at risk for asthma development to test the hypothesis that 3
He MRI measures of ventilation and pulmonary microstructure are related to lung function and history of viral illness. The results show that the lungs of children with asthma have more and larger ventilation defects (i.e. larger VDS) and smaller lung microstructure (i.e. smaller
) relative to non-asthmatic children in this cohort. The association between asthma and ventilation defects in this pediatric population is noteworthy because ventilation defects are a known characteristic of adult asthma.12, 13, 31
To the authors’ knowledge, this study has shown, for the first time, that such defects are present in pre-adolescent asthma subjects. Interestingly, girls as a group also had significantly higher VDS compared to boys, which is an unanticipated result that may foreshadow more pronounced decreases in lung function in girls compared to boys post-adolescence.32
Children who experienced an HRV-wheezing illness during the first three years of life also had increased VDS and smaller
than those who did not. The association of differences in lung microstructure at age 9 or 10 years with history of wheezing in early childhood is a noteworthy finding since it potentially links a measurable lung phenotype with an early childhood risk factor. Moreover, recent studies are finding a strong link between therapeutic response and measures of small airway function in adult asthma33
suggesting a regional bio-marker of small airways disease early in progression may be useful for monitoring long term responses to therapy.
As a measure of regional ventilation, the VDS has been linked to obstructive physiology in prior studies of asthma. In asthmatic adults, studies have observed a significant correlation between ventilation defects and both FEV1
(% of predicted) and the ratio of FEV1
to forced vital capacity (FVC).12, 14
However, in our cohort, VDS did not correlate significantly with PFT measures, and spirometry measures in the groups were similar. Previous studies have shown that spirometry is often normal in children with asthma,34
and our findings suggest that regional measures of obstruction on MRI may be more sensitive indicators of pathologic changes in childhood asthma before these abnormalities are discernible using conventional spirometry. In contrast, IOS measures, such as reactance, resistance, and frequency dependence (R5–R20), were significantly different for both asthma and HRV with wheeze consistent with changes on imaging and possibly indicative of small airway differences between these groups. In addition, there was no significant correlation between
and VDS even though both metrics were significantly different between subjects with and without asthma. The two measures are therefore likely capturing different regional components that are both aspects of the asthma phenotype evaluated in this cohort.
In the current study,
was found to be approximately 15 μm (5%) smaller in children with asthma compared to children without asthma. The mechanism underlying this difference remains unknown. One explanation might be differences in lung inflation affecting the small airway dimensions such as air trapping or atelectasis. A decrease in small airway and alveolar dimensions is opposite to the expected trend if focal air trapping alone were the explanation. Alternatively, regional atelectasis could reduce
in subjects with asthma. These areas should then correlate strongly with areas of ventilation defect, but VDS showed no correlation with
. We therefore speculate that dimensions of the lung microstructure of children with asthma are smaller than those of healthy children. This interpretation is further supported by significant correlations of both
and SSDX with specific IOS measures, AX and X5 (see Table E3 in this article’s Online Repository), that are known to be sensitive to peripheral airway changes. In addition, the SSDX was negatively correlated with
, indicating that children with greater heterogeneity of lung microstructure had smaller microstructural dimension on average. In contrast, studies of ADC, which is also directly related to alveolar and small airway dimensions, have shown the opposite relationship in adults.13, 31, 35
Clearly, further study is needed to better understand the mechanisms underlying this apparent difference between measures of lung microstructure in childhood and adult asthma, but one explanation would implicate smaller airway dimensions as predisposing children to factors leading to wheeze and airway obstruction. Alternatively, some element of peripheral airway remodeling and inflammation may already be occurring in childhood asthma. Longitudinal imaging of the same cohort of children into early adulthood is planned, which should shed light on progressive changes through puberty and adulthood.
There are several limitations to the present study, chief of which is the small sample size. This is by definition a pilot study, since to the best of the authors’ knowledge it is the first time childhood asthma has been investigated systematically with the hyperpolarized noble gas MRI technique. Findings in this cohort may not reflect the general population, because all subjects in the current study had a parent with a history of asthma or respiratory allergies. In addition, to increase the chances of observing differences in the imaging studies, subjects were recruited for imaging if lung function, as determined by FEV1, fell in the highest or lowest quartile of the entire COAST cohort. The decision to seek equal numbers of subjects who did and did not have HRV infection with MSI before the first birthday also may have biased this cohort compared to the general population of 9- and 10-year-olds.
In conclusion, significant signs of regional obstruction and structural change were observed using 3He MRI in the lungs of children with mild to moderate asthma. These imaging measurements provide evidence that childhood asthma is associated with reduced dimensions of small airways and alveolar spaces, which contrasts with findings in adults and further suggests that there are age-related differences in structural features of asthma. Moreover, the observed differences in the extent of ventilation defects between prepubescent girls and boys may be a foreshadowing for the subsequent development of physiological abnormalities during adolescence when incidence and prevalence rates for asthma undergo noticeable shifts for unknown reasons. Overall, these novel observations indicate that 3He MRI can provide new insights into patterns of regional ventilation and peripheral airway changes in asthma, and that this non-invasive technique may be useful to identify mechanisms of disease expression and progression in childhood asthma.