Eric A. Hoffman

Purpose Metronome-paced tachypnea (MPT) is a validated technique to induce dynamic hyperinflation assessed with spirometry. But spirometry cannot directly measure end-expiratory lung volume (EELV), which is a key metric of hyperinflation. We implemented MPT with cine pulmonary MRI to test if MRI measured dynamic hyperinflation relates to hyperinflation in COPD. Methods and Materials SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) is a prospective cohort study that has enrolled 2,981 participants across four strata (never smokers, smokers without COPD, mild/moderate COPD, and severe COPD) with the goal of identifying new COPD subgroups and intermediate markers of disease progression. The SPIROMICS Heart Failure (HF) Study is evaluating cardiopulmonary interactions in COPD. During 2D coronal cine pulmonary MRI, participants at one site performed …

Objective Assess regional changes in CT-based ventilation and perfusion matching (V/Q) after sildenafil in smokers and non-smokers. Methods Cohort of 79 smokers and 55 non-smokers were used in this study: 68/66 F/M; 21-65yrs; 18-38 BMI. All subjects had one CT scan at TLC, as well as two contrast-enhanced dual-energy CT (DECT) scans at FRC (80 and Sn150kV, Siemens SOMATOM Force). DECT scans were acquired pre-and post-administration of 20mg oral sildenafil The effective doses for the non-contrast and DECT scans were 0.44 and 2.45 mSv, respectively. Half concentration of 370 mg/mL Iopamidol was delivered to the right antecubital vein at 4 mLsec-1, 17 seconds prior to onset of scanning and continuing for the duration of the scan. TLC-to-FRC image registration was used to calculate regional volume change, a surrogate of regional ventilation (V). Material decomposition on the DECT images …

Rationale We characterized idiopathic pulmonary fibrosis (IPF) sub-phenotypes from quantitative inspiratory computed tomography (CT)-based regional lung structure-function characteristics, pulmonary function test (PFT), and demographics. Methods and Materials Inspiratory CTs, PFT results, and demographics were collected from 152 IPF (age= 70±7, M: F= 124: 28) patients from 6 institutions in Korea (under IRB approval and with subject consent). 45 multiscale airway and lung structurefunction features were derived through qCT analysis using commercial (VIDA Diagnostics, Coralville, IA) and in-house software. Principal component analysis, k-means clustering, and Kruskal-Wallis with Dunn’s post-hoc test were used for sub-phenotyping and inter-cluster comparison (statistical significance by p< 0.05). Random Forest was used to predict the cluster membership of a subject. Shapley Additive exPlanations …

Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known. Molecular markers for identifying any mental disorder are currently lacking. Gene expression profiling during the triggering and development of PTSD may be informative of its onset and course. We used oligonucleotide microarrays to measure peripheral blood mononuclear cell (PBMC) gene expression of trauma survivors at the emergency room and 4 months later. Gene expression signatures at both time points distinguished survivors who met DSM-IV diagnostic criteria for PTSD at 1 and 4 months, from those who met no PTSD criterion. Expression signatures at both time points …

Pulmonary emphysema, the progressive, irreversible loss of lung tissue, is conventionally categorized into three subtypes identifiable on pathology and on lung computed tomography (CT) images. Recent work has led to the unsupervised learning of ten spatially-informed lung texture patterns (sLTPs) on lung CT, representing distinct patterns of emphysematous lung parenchyma based on both textural appearance and spatial location within the lung, and which aggregate into 6 robust and reproducible CT Emphysema Subtypes (CTES). Existing methods for sLTP segmentation, however, are slow and highly sensitive to changes in CT acquisition protocol. In this work, we present a robust 3-D squeeze-and-excitation CNN for supervised classification of sLTPs and CTES on lung CT. Our results demonstrate that this model achieves accurate and reproducible sLTP segmentation on lung CTscans, across two independent cohorts and independently of scanner manufacturer and model.

RATIONALE The upper airway plays an important role in potentially modifying air pollutant and drug delivery to the lower airway in asthma. We investigated the altered upper airway in asthma and its impact on regional lung structural and functional features by quantitative computed tomography (qCT) analysis. Methods Upper airway CT, inspiratory (total lung capacity) and expiratory (functional residual capacity) lung CTs, and clinical data were collected from 83 (55 after age matching, p= 0.059) patients with asthma (64.7±12.4 y, M: F= 53: 30) and 26 healthy controls (56.6±5.1 y, M: F= 18: 8) enrolled at Jeonbuk National University Hospital (Jeonju, Korea). ITK-SNAP, VIDA Vision 2.2, and in-house qCT software were used for segmentation and regional structurefunction analysis of the upper airway and the lung. Wilcoxon rank-sum test and Pearson’s correlation were used for statistical analysis. Results Asthma …

RATIONALE Acute respiratory distress syndrome (ARDS) is characterized by heterogeneous lung inflammation and impairments in gas exchange. While mechanical ventilation is vital to its management, prolonged or inappropriate use can result in ventilator-induced lung injury (VILI), especially in the presence of existing structural heterogeneity. Multi-frequency ventilation (MFV) may address these challenges by ventilating the lungs with multiple simultaneous frequencies, to achieve more uniform distribution of gas flow in a mechanically heterogeneous lung. In this study, we hypothesized that MFV has the potential to reduce further lung injury in a porcine model of ARDS when compared to conventional mechanical ventilation (CMV), based on various quantitative computed tomographic (CT) imaging biomarkers. METHOD Twelve anesthetized pigs (36.7-70.0 kg) received volumetric 3D CT scans during static …

Rationale Asthma patients that develop persistent airflow obstruction (PAO) have worse long-term outcomes. Quantitative CT (qCT) allows detailed examination of structure-function relationship in obstructive lung disease which we applied to asthma patients with PAO in the Severe Asthma Research Program (SARP). Methods Clinical and CT data were obtained from patients enrolled in the SARP-3. We included 472 patients, who had at least 3 visits over at least one year, of which 204 had qCT analysis via Vision 2.2 (VIDA) and in-house software. PAO was defined as postbronchodilator FEV1/FVC< Lower Limit of Normal (GLI predicted). Patients were classified in 5 groups depending on the spirometry results during follow up: 1= Persistent PAO, 2= Never PAO, 3= Intermittent PAO, 4= Initial PAO then resolves and 5= initial No PAO then develops PAO. qCT metrics include air trapping (AirT%) as regions of …

RATIONALE: The long-term sequalae of COVID-19 survivors who recovered from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains uncertain. A recent study involving post-COVID-19 individuals who underwent examination approximately 112 days after their initial COVID-19 diagnosis identified two distinct clusters from computed tomography (CT) lung images. Cluster 1 (C1) consisted mainly of females exhibiting small airway diseases, whereas Cluster 2 (C2) was primarily composed of older individuals showing interstitial fibrotic-like patterns. This work aims to investigate airway resistance and particle deposition in these clusters. METHODS: The study enrolled 245 individuals, with 140 of them being individuals who had recovered from SARS-CoV-2 and were attending post-COVID-19 outpatient visits at the University of Iowa Hospitals & Clinics for follow-up examinations. The …

Rationale Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives We hypothesised that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods We recruited 431 current smokers (median age 39 years, 16 pack-years smoked) and recorded symptoms by the COPD Assessment Test (CAT), spirometry and quantitative thoracic CT (QCT) scans at study entry. These scans results were compared to 67 never smoking controls. 368 participants were followed every six months with measurement of post-bronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age and sex was related to the initial QCT appearances and symptoms, measured with the CAT. Measurements and Main Results There …

Rationale Mismatch of airway size and lung volume, captured in the dysanapsis index, has been shown to impart a significant risk of COPD regardless of smoking status, and a significant risk factor for other diseases. Because of the close developmental relationship between the bronchial and arterial trees we have sought to establish the implications of arterial tree size relative to lung size (pulmonary arterial dysanapsis). Methods A database of 80 semi-automatically segmented pulmonary arterial and venous trees was created from dual-energy contrast-enhanced CT scans taken at FRC (Functional Residual Capacity), at an upsampled isotropic resolution of 0.38 mm. The segmentations include the trees from the pulmonary trunk, midway into the lung periphery, using a consistent watershed segmentation at 0.6 mm scale, and quality controlled by 2 observers including a boardcertified radiologist. Clinical and …

Rationale Alterations in chest wall dimensions and ventilatory patterns are hallmarks of the development of chronic obstructive pulmonary disease (COPD). This abstract presents CT-based automated measures of lung volume associated deformation of individual ribs and evaluates their reproducibility. Methods Matching landmark locations in corresponding ribs in total lung capacity (TLC) and functional residual capacity (FRC) chest CT images were detected using a proprietary algorithm involving deep learning and morphology-based rib segmentation, local scale-based centerline detection, and B-spline-based uniform landmark location (Figure 1 (a)). Transverse sweep area, transverse deformation, and caudocranial deformation were computed for individual ribs 2 to 9 using matching landmarks at TLC and FRC scans after alignment of the heads of corresponding ribs (Figures 1 (bd)). Transverse sweep area …

BackgroundRecent studies, based on clinical data, have identified sex and age as significant factors associated with an increased risk of long COVID. These two factors align with the two post-COVID-19 clusters identified by a deep learning algorithm in computed tomography (CT) lung scans: Cluster 1 (C1), comprising predominantly females with small airway diseases, and Cluster 2 (C2), characterized by older individuals with fibrotic-like patterns. This study aims to assess the distributions of inhaled aerosols in these clusters.Methods140 COVID survivors examined around 112 days post-diagnosis, along with 105 uninfected, non-smoking healthy controls, were studied. Their demographic data and CT scans at full inspiration and expiration were analyzed using a combined imaging and modeling approach. A subject-specific CT-based computational model analysis was utilized to predict airway resistance and …

RationaleDysanapsis refers to developmental mismatch between airway tree caliber and lung size. Our group has demonstrated that larger airway tree caliber is associated with interstitial lung abnormalities on chest CT in a prospective cohort of communitydwelling adults. Here we present validation in two additional independent cohorts: the Canadian Cohort of Obstructive Lung Disease (CanCOLD), a nested case-control study, and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a longitudinal case-control study. Methods Dysanapsis was defined as the mean of airway lumen diameters measured at 19 standard locations from trachea to subsegment divided by the cube root of total lung volume on full lung CT scans (airway to lung ratio). Interstitial lung abnormalities (ILA) were visually assessed by trained readers unaware of other participant information (CanCOLD only …

Introduction Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. Methods Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomic locations and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well …

Rationale Loci of COPD susceptibility identified by genome-wide association studies (GWAS) account for only a small proportion of observed heritability. Such missing heritability suggests environmental factors, including tobacco smoke and airway microbiome dysbiosis, result in epigenetic alterations that impact disease susceptibility by contributing to perturbations in COPD-relevant pathobiology. Methods We isolated DNA from bronchoscopic lower airways brushings of n= 72 participants with> 20 pack-years smoking history from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS), using the Illumina Infinium Methylation EPIC BeadChip Array to assess proportion of DNA methylation (β) spanning 689,937 CpG sites. Regression models based on epigenome-wide association study (EWAS) tested for differentially methylated CpG probes (DMPs) between those with moderate-to …

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.

Rationale Patients with severe asthma are at increased risk for coincident metabolic diseases including obesity, diabetes, and hypertension. An association between asthma and metabolic dysfunction-associated fatty liver disease (MAFLD) has also been reported, but the actual incidence of MAFLD in patients with pre-existing asthma is unknown. MAFLD is often attributed to obesity and chronic steroid use in patients with asthma, but prospective studies investigating the biologic linkage between these two diseases has not been done. We hypothesize a higher prevalence of MAFLD in the Severe Asthma Research Program (SARP) cohort compared to the general US population, and that MAFLD in asthma is associated with elevated plasma IL-6 levels and decreased lung function. Methods Baseline and longitudinal data from the multicenter SARP3 cohort were analyzed (median follow-up 5 years). Computed …

RATIONALE Lung density, quantified by computed tomography (CT), plays a pivotal role in assessment and monitoring of changes in lung condition. Longitudinal evaluation relies on consistent measurements of lung density. However, scanner technologies vary over time, which may negatively influence the reproducibility of measurements. One recent advancement has been the emergence of photon-counting CT (PCCT) scanners, providing enhanced spatial resolution, image contrast, and lower noise compared to conventional energy-integrating CT (EICT) scanners. There is a need to investigate the reproducibility of lung density measurements within PCCT scanners and compare them against EICT scanners. The purpose of this study was to investigate the intra-and inter-scanner reproducibility of lung density quantification in PCCT compared to EICT scanners at multiple centers. METHODS Three distinct …

Conclusions: Eligibility criteria to define ‘healthy’include a substantial proportion of individuals with lung pathology that is associated with deficits in lung function, lower socio-economic status and healthcare access, and higher mortality.This abstract is funded by: This research was supported by CLA/CRRN MD Studentship, R01-HL130506, R01-HL121270, R01-HL077612, contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences …