Association of abnormal pulmonary vasculature on CT scan for COVID-19 infection with decreased diffusion capacity in follow up: A retrospective cohort study.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a respiratory viral illness causing pneumonia and systemic disease. Abnormalities in pulmonary function tests (PFT) after COVID-19 infection have been described. The determinants of these abnormalities are unclear. We hypothesized that inflammatory biomarkers and CT scan parameters at the time of infection would be associated with abnormal gas transfer at short term follow-up. METHODS: We retrospectively studied subjects who were hospitalized for COVID-19 pneumonia and discharged. Serum inflammatory biomarkers, CT scan and clinical characteristics were assessed. CT images were evaluated by Functional Respiratory Imaging with automated tissue segmentation algorithms of the lungs and pulmonary vasculature. Volumes of the pulmonary vessels that were ≤5mm (BV5), 5-10mm (BV5_10), and ≥10mm (BV10) in cross sectional area were analyzed. Also the amount of opacification on CT (ground glass opacities). PFT were performed 2-3 months after discharge. The diffusion capacity of carbon monoxide (DLCO) was obtained. We divided subjects into those with a DLCO <80% predicted (Low DLCO) and those with a DLCO ≥80% predicted (Normal DLCO). RESULTS: 38 subjects were included in our cohort. 31 out of 38 (81.6%) subjects had a DLCO<80% predicted. The groups were similar in terms of demographics, body mass index, comorbidities, and smoking status. Hemoglobin, inflammatory biomarkers, spirometry and lung volumes were similar between groups. CT opacification and BV5 were not different between groups, but both Low and Normal DLCO groups had lower BV5 measures compared to healthy controls. BV5_10 and BV10 measures were higher in the Low DLCO group compared to the normal DLCO group. Both BV5_10 and BV10 in the Low DLCO group were greater compared to healthy controls. BV5_10 was independently associated with DLCO<80% in multivariable logistic regression (OR 1.29, 95% CI 1.01, 1.64). BV10 negatively correlated with DLCO% predicted (r = -0.343, p = 0.035). CONCLUSIONS: Abnormalities in pulmonary vascular volumes at the time of hospitalization are independently associated with a low DLCO at follow-up. There was no relationship between inflammatory biomarkers during hospitalization and DLCO. Pulmonary vascular abnormalities during hospitalization for COVID-19 may serve as a biomarker for abnormal gas transfer after COVID-19 pneumonia.

The short-term effects of ORKAMBI (lumacaftor/ivacaftor) on regional and distal lung structures using functional respiratory imaging.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has shown modest benefits in previous research, but the exact effects in the cystic fibrosis (CF) lung remain unclear. This study aims to offer novel information on the mode of action of the cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drug by assessing lung structure and function using functional respiratory imaging (FRI). METHODS: CF patients aged ⩾12 years homozygous for F508del were recruited in an open-label study. Before and after 12 weeks of treatment with LUM/IVA, FRI was used to visualize regional information, such as air trapping, lobar volume and airway wall volume. Secondary outcomes included the CF-CT scoring system, spirometry, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaire, exercise tolerance and nutritional status. RESULTS: Of the 12 patients enrolled in the study, 11 completed all study visits. Concerning the FRI parameters, hyperinflation of the lung decreased, indicated by a reduction in air trapping and lobar volume at expiration. Also, a decrease in airway wall volume and a redistribution of pulmonary blood volume were noted, which might be related to a decrease in mucus impaction. Airway resistance, airway volume, internal airflow distribution and aerosol deposition pattern did not show significant changes. No significant improvements were found in any of the CF-CT scores or in the spirometric parameters. Other secondary outcomes showed similar results compared with previous research. Correlations at baseline were found between FRI and conventional outcomes, including physical functioning, spirometry and CF-CT scores. CONCLUSIONS: LUM/IVA decreased lung hyperinflation in combination with a potential decrease in mucus impaction, which can be related to an improved mucociliary transport. These results indicate that several FRI parameters, reflecting regional and distal lung structures, are more sensitive to changes caused by LUM/IVA than conventional respiratory outcomes.

Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional study.

BACKGROUND: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. METHODS: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. RESULTS: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. CONCLUSIONS: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Functional respiratory imaging provides novel insights into the long-term respiratory sequelae of bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional respiratory imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD using FRI and to correlate these findings with the clinical presentation. METHODS: We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and computed tomography (CT) (at total lung capacity (TLC) and functional residual capacity (FRC)) with FRI. CT images were also assessed using the Aukland scoring system. RESULTS: BPD patients had lower forced expiratory volume in 1 s to forced vital capacity ratio (p=0.02) and impaired diffusion capacity (p=0.02). Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01), but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images. CONCLUSION: This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.

The Role of Functional Respiratory Imaging in Treatment Selection of Children With Obstructive Sleep Apnea and Down Syndrome.

STUDY OBJECTIVES: The complexity of the pathogenesis of obstructive sleep apnea (OSA) in children with Down syndrome (DS) is illustrated by a prevalence of residual OSA after adenotonsillectomy. The aim of this study was to investigate whether upper airway imaging combined with computation fluid dynamics could characterize treatment outcome after adenotonsillectomy in these children. METHODS: Children with DS and OSA were prospectively included. All children underwent an evaluation of the upper airway and an ultra-low dose computed tomography scan of the upper airway before adenotonsillectomy. The upper airway tract was extracted from the scan and combined with computational fluid dynamics. Results were evaluated using control polysomnography after adenotonsillectomy. RESULTS: Thirty-three children were included: 18 boys, age 4.3 ± 2.3 years, median body mass index z-score 0.6 (-2.9 to 3.0), and median obstructive apnea-hypopnea index was 15.7 (3-70) events/h. The minimal upper airway cross-sectional area was significantly smaller in children with more severe OSA (P = .03). Nineteen children underwent a second polysomnography after adenotonsillectomy. Seventy-nine percent had persistent OSA (obstructive apneahypopnea index > 2 events/h). A greater than 50% decrease in obstructive apnea-hypopnea index was observed in 79% and these children had a significantly higher volume of the regions below the tonsils. CONCLUSIONS: This is the first study to characterize treatment outcome in children with DS and OSA using computed tomography upper airway imaging. At baseline, children with more severe OSA had a smaller upper airway. Children with a less favorable response to adenotonsillectomy had a smaller volume of regions below the tonsils, which could be due to enlargement of the lingual tonsils, glossoptosis, or macroglossia. COMMENTARY: A commentary on this article appears in this issue on page 501.

Predicting the effect of treatment in paediatric OSA by clinical examination and functional respiratory imaging.

OBJECTIVE: The aim of this study was to investigate whether functional respiratory imaging (FRI) or clinical examination could predict treatment outcome for obstructive sleep apnea (OSA) in normal-weight, non-syndromic children. METHODS: Normal weight children diagnosed with OSA by polysomnography were prospectively included. All children got a thorough evaluation and an ultra-low dose computed tomography scan of the upper airway (UA). A 3-D reconstruction was built combined with computational fluid dynamics for FRI. Decisions on the need and type of surgery were based upon findings during drug-induced sleep endoscopy. A second polysomnography was performed 3-12 months after surgery. RESULTS: Ninety-one children were included: 62 boys, 5.0 ± 2.7 years, and BMI z-score of -0.1 ± 1.2. Children with more severe OSA had a smaller volume of the overlap region between the adenoids and tonsils. Nineteen out of 60 patients had persistent OSA (oAHI >2/h). A lower conductance in the UA and a higher tonsil score predicted successful treatment. CONCLUSIONS: A less constricted airway, as characterized by both FRI and a lower tonsil score, was associated with a less favorable response to (adeno) tonsillectomy. Further studies after treatment using FRI and DISE are warranted to further characterize the UA of these subjects.

Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?

BACKGROUND: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF. METHODS: In- and expiratory CT-scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses. RESULTS: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations. CONCLUSIONS: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.

Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products.

In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of ß-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.

Upper airway imaging in pediatric obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome in children is a manifestation of sleep-disordered breathing and associated with a number of complications. Structural narrowing of the upper airway in combination with inadequate compensation for a decrease in neuromuscular tone is an important factor in the pathogenesis. Adenotonsillar hypertrophy is the most important predisposing factor. However, many other causes of craniofacial defects may coexist. Additionally, the pathogenesis of narrowing is more complex in certain subgroups such as children with obesity, craniofacial malformations, Down syndrome or neuromuscular disorders. The diagnosis of obstructive sleep apnea is based on an overnight polysomnography. This investigation is expensive, time consuming and not widely available. In view of the major role of structural narrowing, upper airway imaging could be a useful tool for investigating obstructive sleep apnea and in establishing the site(s) of obstruction. Several radiological techniques (lateral neck radiography, cephalometry, computerized tomography, magnetic resonance imaging and post-processing of these images using computational fluid dynamics) have been used to investigate the role of structural alterations in the pathogenesis. We reviewed the literature to examine if upper airway imaging could replace polysomnography in making the diagnosis and if imaging could predict the effect of treatment with a focus on adenotonsillectomy. There is a limited number of high quality studies of imaging predicting the effect of treatment. To avoid unnecessary risks and ineffective surgeries, it seems crucial to couple the exact individual anatomical risk factor with the most appropriate treatment. We conclude that imaging could be a non-invasive tool that could assist in selection of treatment.

Functional respiratory imaging as a tool to personalize respiratory treatment in patients with unilateral diaphragmatic paralysis.

A completely different treatment approach was chosen for 2 patients with unilateral diaphragmatic paralysis and complaints of dyspnea despite similar anatomic and physiologic abnormalities. These decisions were supported by results obtained by functional respiratory imaging (FRI). FRI generated functional information on lobar ventilation and local drug deposition. In the first patient, some lobes were poorly ventilated, and drug deposition simulation showed that some regions were undertreated. This patient underwent diaphragmatic plication to restore ventilation. In the second patient, all lobes were still ventilated. A conservative approach with regular follow-ups was chosen to wait for spontaneous recovery of the diaphragmatic function. Both patients improved subjectively and objectively. These cases demonstrate how novel medical imaging techniques such as FRI can be used to personalize respiratory treatment in patients with unilateral diaphragmatic paralysis.

Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients.

BACKGROUND: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy. METHODS: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months. RESULTS: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol. CONCLUSION: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial.

Novel imaging techniques using computer methods for the evaluation of the upper airway in patients with sleep-disordered breathing: a comprehensive review.

Patients with sleep related breathing disorders (SRBD) can be treated with nasal continuous positive airway pressure (nCPAP) or with several upper airway (UA) interventions. While nCPAP is almost always effective when clinically well tolerated, the therapeutic outcome of UA surgery and UA devices is difficult to predict. The improvement of our capability to perform the latter predictions more accurately is of great clinical importance since it will prevent patients to be treated with ineffective, sometimes irreversible, techniques. In this review we describe the importance of new imaging methods in this respect. We first refer to the most important pathophysiological mechanisms known so far to play a role in SRBD, indicating that functional imaging could elucidate these mechanisms in a patient specific manner. Then we describe the new technologies that make UA imaging more functional referring to the data as they are presently available. Finally we summarise the studies that do indicate that the use of functional imaging of the UA in SRBD patients may significantly help to predict the clinical outcome after UA interventions.