Lung Physiological Variations in COVID-19 Patients and Inhalation Therapy Development for Remodeled Lungs

In response to the unmet need for effective treatments for symptomatic patients, research efforts of inhaled therapy for COVID-19 patients have been pursued since the pandemic began. However, inhalation drug delivery to the lungs is sensitive to the lung anatomy and physiology, which can be significantly altered due to the viral infection. The ensued ventilation heterogeneity will change distribution and thus dosimetry of inhaled medications, rendering previous correlations concepts? of pulmonary drug delivery in healthy lungs less reliable. In this study, we first reviewed the recent developments of inhaled therapeutics and vaccines, as well as the latest knowledge of the lung structural variations documented by CT of COVID-19 patients' lungs. We then quantified the volume ratios of the poorly aerated lungs and non-aerated lungs in eight COVID-19 patients, which ranged 2-8% and 0.5-3%, respectively. The need to consider the diseased lung physiologies in estimating pulmonary delivery was emphasized. Diseased lung geometries with varying lesion sites and complexities were reconstructed using Statistical Shape Modeling (SSM). A new segmentation method was applied that could generate patient-specific lung geometries with an increased number of branching generations. The synergy of the CT-based lung segmentation and SSM-based airway variation showed promise for developing representative COVID-infected lung morphological models and investigating inhalation therapeutics in COVID-19 patients. Doi: 10.28991/SciMedJ-2021-0303-1 Full Text: PDF

The validity of shortened multiple breath washout testing using sulphur hexafluoride in the assessment of patients with COPD

IntroductionChronic Obstructive Pulmonary Disease (COPD) affects the small airways and is associated with ventilation heterogeneity. There is little data on the Multiple Breath Washout (MBW) in patients with COPD particularly the variability over eight weeks, using a shortened sulphur hexafluoride (SF6) washout. This work evaluated the repeatability of the LCI1/40 and LCI1/20 among subjects with COPD and compared to spirometry and clinical markers.MethodsThe MBW was performed on patients with COPD to determine ventilation heterogeneity globally (Lung Clearance Index (LCI)), at conductive (Scond) and acinar (Sacin) levels. The LCI was repeated in triplicate and measured at a traditional 1/40th washout and retrofitted to a shortened 1/20th end tidal SF6 concentration washout. Tests were repeated after 20 min and eight weeks to determine within and between visit repeatability and compared with spirometry.Results84 subjects were recruited to perform LCI and spirometry with 20 subjects performing the repeatability protocol. There were weak correlations between FEV1 percent predicted and LCI1/40th r=−0.311 (p=0.02), and LCI1/20th r=−0.40 (p<0.01). The LCI demonstrated excellent within and good between visit repeatability for both a 1/40th and 1/20th washout (ICC≥0.80). There was a statistically significant strong correlation between LCI1/40th and a shortened LCI1/20 0.86 (p<0.01).ConclusionsThe LCI is repeatable within and between visits. There are weak correlations with measures of spirometry. A shortened LCI1/20th starting concentration correlates highly with a 1/40th washout which may encourage clinical use.

Ventilation heterogeneity in children with severe asthma

Small airway disease, characterised by ventilation heterogeneity (VH), is present in a subgroup of patients with asthma. Ventilation heterogeneity can be measured using multiple breath washout testing. Few studies have been reported in children. We studied the relationship between VH, asthma severity, and spirometry in a cross-sectional observational cohort study involving children with stable mild-moderate and severe asthma by GINA classification and a group of healthy controls. Thirty-seven participants aged 5–16 years completed multiple breath nitrogen washout (MBNW) testing (seven controls, seven mild-moderate asthma, 23 severe asthma). The lung clearance index (LCI) was normal in control and mild-moderate asthmatics. LCI was abnormal in 5/23 (21%) of severe asthmatics. The LCI negatively correlated with FEV1z-score.Conclusion: VH is present in asthmatic children and appears to be more common in severe asthma. The LCI was significantly higher in the cohort of children with severe asthma, despite no difference in FEV1 between the groups. This supports previous evidence that LCI is a more sensitive marker of airway disease than FEV1. MBNW shows potential as a useful tool to assess children with severe asthma and may help inform clinical decisions. What is Known:• Increased ventilation heterogeneity is present in some children with asthma• Spirometry is not sensitive enough to detect small airway involvement in asthma What is New• Lung clearance index is abnormal in a significant subgroup of children with severe asthma but rarely in children with mild-moderate asthma• Our data suggests that LCI monitoring should be considered in children with severe asthma

Ventilation Heterogeneity in Asthma and COPD: The Value of the Poorly Communicating Fraction as the Ratio of Total Lung Capacity to Alveolar Volume

<b><i>Background:</i></b> The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (<i>S</i>_cond) and acinar (<i>S</i>_acin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement. <b><i>Objectives:</i></b> Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups. <b><i>Method:</i></b> We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test. <b><i>Results:</i></b> Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and <i>S</i>_acin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (<i>p</i> &#x3c; 0.05) and <i>S</i>_acin (<i>p</i> &#x3c; 0.05), but not with <i>S</i>_cond. Lastly, COPD patients with PCF &#x3e;30% were highly likely to have a value ≥2 of the mMRC dyspnea scale. <b><i>Conclusions:</i></b> These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique.

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters

BackgroundMultiple breath washout (MBW) using sulfur hexafluoride (SF6) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF6-MBW reference values in pulmonary healthy adults.MethodsWe evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20–88 years). Lung clearance index (LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from triplicate SF6-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI2.5) and 5% (LCI5) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile.ResultsAge was the only meaningful parameter influencing SF6-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in Sacin and 10% (CI 2% to 22%) in Scond. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in Sacin and 3% (CI 0% to 13%) in Scond.ConclusionSF6-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF6-MBW outcome parameters over the whole age range.Trial registration numberNCT04099225.

Airway closure is the predominant physiological mechanism of low ventilation seen on hyperpolarized helium-3 MRI lung scans

Hyperpolarized helium-3 MRI (3He MRI) provides detailed visualization of low- (hypo- and non-) ventilated lung. Physiological measures of gas mixing may be assessed by multiple breath nitrogen washout (MBNW) and of airway closure by forced oscillation technique (FOT). We hypothesize that in patients with asthma, areas of low-ventilated lung on 3He MRI are the result of airway closure. Ten control subjects, ten asthma subjects with normal spirometry (non-obstructed), and ten asthmatic subjects with reduced baseline lung function (obstructed) attended two testing sessions. On visit one, baseline plethysmography was performed followed by spirometry, MBNW and FOT assessment pre- and post-methacholine challenge. On visit two, 3He MRI scans were conducted pre- and post-methacholine challenge. Post methacholine the volume of low ventilated lung increased from 8.3% to 13.8% in the non-obstructed group (p = 0.012) and from 13.0% to 23.1% in the obstructed group (p=0.001). In all groups, the volume of low ventilation from 3He MRI correlated with a marker of airway closure in obstructive subjects, Xrs (6Hz) and the marker of ventilation heterogeneity Scond with r2 values of 0.61 and 0.56 respectively. The change in Xrs (6Hz) correlated well (r2 = 0.45), while the change in Scond was largely independent of, the change in low ventilation volume (r2=0.13). The only significant predictor of low ventilation volume from the multi-variate analysis was Xrs (6Hz). This is consistent with the concept that regions of poor or absent ventilation seen on 3He MRI are primarily the result of airway closure.