Discussion
Children with problematic wheeze/asthma and significant VH, identified
by VHI % in the upper 75th %ile, had a severe
clinical phenotype with greater airflow limitation, bronchodilator
reversibiity, and markers of type 2 inflammation. BAL from bronchial
segments to lobes with ventilation defects had greater eosinophils, and
children with VHI % in the upper 75th %ile
accordingly had greater eosinophilic and neutrophilic BAL granulocyte
patterns compared to children in the lower 25th %ile.
These results indirectly support an important role of eosinophilic
debris and type 2 inflammations in the formation of regions of
hypoventilation in asthma. The results also show that the VHI %, which
defines both the non- and hypoventilated volume compartments in asthma,
is likely a better predictor of disease severity in asthma compared to
the traditional indicator, the Vdef %.
Original studies in patients with asthma based on hyperpolarized gas MRI
used ventilation defect counts as estimates of VH3-4,6-7. Recently, analytic platforms5,11-12,14 were developed which quantified the Vdef %
as a fraction of the total lung volume. In a previous report11 in children with moderate to severe asthma, the
median Vdef % was 1.3%, identical to the Vdef % in the present study.
In this and previous reports, the Vdef % is skewed towards smaller
values in a non-Gaussian distribution; hence we substituted the VHI %
as an alternate VH metric to differentiate clinical features in the
present study. The VHI % is normally distributed and overall performed
better than the Vdef % as a predictor of clinical outcomes. However,
both the VHI % and the Vdef % are global indicators of net VH in the
lung, and vary significantly by anatomic region. A limiting factor in
using total lung VH as a primary outcome to test treatment effects and
exacerbations is insensitivity to regional differences in response which
could be missed by a total lung indicator.
The results of the present study are among the first that we can find
which resolve localized patterns of lung granulocytic inflammation in
asthmatics based on visible ventilation defects. BAL return from lung
lobes with ventilation defects had greater eosinophils. These results
diverge slightly from those of Fain et al based on analysis of regional
air trapping and BAL constituents in adults with asthma10. In that study, the absolute number and percentage
of BAL neutrophils correlated with lung defect volume. The recent
findings of Dunican et al based on CT identify a relationship between
luminal obstruction with mucus plugs and sputum eosinophilia in adults
with asthma 15.
The present study sample has co-morbid features which limits its
generalizability to a broad asthma population. We would expect that the
degree of VH in a community-based sample might be less than in the
present study, enriched in children with severe asthma and inadequate
symptom control. We studied a relatively young sample, whereby past
studies have shown greater VH in older patients with asthma5. We therefore would recommend future studies using
hyperpolarized noble gas imaging with uniform image acquisition
sequences at controlled lung volumes at several centers. This has been
done in a limited way with testing the effects of bronchial thermoplasty
on VH in asthma with promising early results 24.