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.