Early Lung Disease Research Articles

Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in the COPDGene Study.

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Big Things Have Small Beginnings: Clinical Implications of Early Interstitial Lung Disease

Big Things Have Small Beginnings: Clinical Implications of Early Interstitial Lung Disease

Multiple Mechanisms of Action of Sulfodyne®, a Natural Antioxidant, against Pathogenic Effects of SARS-CoV-2 Infection.

Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of NRF2-agonist Sulfodyne®, a stabilized natural Sulforaphane, in cellular and animal models of SARS-CoV-2 infection. In pulmonary or colonic epithelial cell lines, Sulfodyne® elicited a more efficient inhibition of SARS-CoV-2 replication than NRF2-agonists DMF and CDDO. This antiviral activity was not dependent on NRF2 but was associated with the regulation of several metabolic pathways, including the inhibition of ER stress and mTOR signaling, which are activated during SARS-CoV-2 infection. Sulfodyne® also decreased SARS-CoV-2 mediated inflammatory responses by inhibiting the delayed induction of IFNB1 and type I IFN-stimulated genes in infected epithelial cell lines and by reducing the activation of human by-stander monocytes recruited after SARS-CoV-2 infection. In K18-hACE2 mice infected with SARS-CoV-2, Sulfodyne® treatment reduced both early lung viral load and disease severity by fine-tuning IFN-beta levels. Altogether, these results provide evidence for multiple mechanisms that underlie the antiviral and anti-inflammatory activities of Sulfodyne® and pinpoint Sulfodyne® as a potent therapeutic agent against pathogenic effects of SARS-CoV-2 infection.

The Omega-6 Lipid pathway shift is associated with neutrophil influx and structural lung damage in early cysticfibrosis lung disease.

In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters. Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1-5 using a targeted high-performance liquid chromatography-tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression. A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB4 and 6-trans-LTB4 positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB4 was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction. Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.

The predictive role of lung clearance index on FEV1 decline in cystic fibrosis.

The lung clearance index (LCI) is a sensitive lung function index that is used to detect early lung disease changes in children with cystic fibrosis (CF). This study aimed to define the predictive role of baseline LCI, along with other potential factors on the change in forced expiratory volume in one second (FEV1) during one-year follow-up in CF patients who had a percent predicted (pp) FEV1≥80. LCI was concurrently performed on 57 CF patients who had ppFEV1 ≥80 at month zero. The ppFEV1 decline was evaluated prospectively during the one year follow up. The primary outcome of ppFEV1 decline in the study group in one year was dichotomized according to the median value for the decline in ppFEV1, which was 3.7. The LCI value predicting ppFEV1 decline at the end of one year was calculated with receiver operating characteristic curve analysis. Regression analysis was performed. Furthermore, a decision tree was constructed using classification and regression tree methods to better define the potential effect of confounders on the ppFEV1 decline. The LCI value for predicting ppFEV1 decline >3.7% at the end of one year was 8.2 (area under the curve: 0.80) Multivariable regression analysis showed that the absence of the F508del mutation in at least one allele, LCI >8.2 and initial FEV1 z-score were predictors of a ppFEV1 decline >3.7 (p<0.001). Factors altering ppFEV1 decline>3.7% at the end of one-year evaluated by decision trees were as follows: initial FEV1 z-score, type of CFTR mutation, LCI value and initial weight-for-age z-score. LCI is sensitive for predicting ppFEV1 decline in patients with ppFEV1 ≥80 along with the initial FEV1-z-score and type of CFTR mutation.

Comparative sensitivity of early cystic fibrosis lung disease detection tools in school aged children

BackgroundEffective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children. Methods50 CF subjects (mean±SD 11.2 ± 3.5y, range 5–18y) with early lung disease (FEV1≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT). ResultsCT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82 %, MBWTG RV 78 %, LCI 74 %, MBWTG IC 68 % and Sacin 51 %. CPET VO2peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r = 0.55–0.64, p < 0.001) and AT (r = 0.73–0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %. ConclusionsSignificant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening – A nationwide observational study

BackgroundNon-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. MethodsLung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 – 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. ResultsLCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. ConclusionsThe LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.

EPS7.08 Improved diagnosis of early aspergillus lung disease in cystic fibrosis (IDEAL)

EPS7.08 Improved diagnosis of early aspergillus lung disease in cystic fibrosis (IDEAL)

Measuring lung diffusing capacity: an opportunity for improved medical surveillance and disability evaluation of coal miners

ObjectivesSpirometry is the primary lung function test utilised for medical surveillance and disability examination for coal mine dust lung disease. However, spirometry likely underestimates physiologic impairment. We sought to characterise...

WS11.03 Early cystic fibrosis lung disease in the TRACK-CF cohort: what longitudinal multiple-breath washout and chest magnetic resonance imaging teach us

WS11.03 Early cystic fibrosis lung disease in the TRACK-CF cohort: what longitudinal multiple-breath washout and chest magnetic resonance imaging teach us

A vexing case of non-healing ulcers with interstitial lung disease

Clinically amyopathic dermatomyositis is a subset of dermatomyositis that does not have any clinical evidence of muscle inflammation. Hence, it frequently poses a diagnostic challenge to the clinician. Here, we present a middle-aged farmer who presented only with multiple non-healing ulcers and was eventually found to be having early interstitial lung disease. He was finally diagnosed with anti- melanoma differentiation-associated gene 5 dermatomyositis and was started on aggressive immunosuppressants.

Plasma metabolomics and quantitative interstitial abnormalities in ever-smokers

BackgroundQuantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality.MethodsIn 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography–mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini–Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst.ResultsWe found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways.ConclusionsMetabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers.

The Effect of Ferritin Level on Respiratory Functions in Patients with β-Thalassemia Major

Introduction-Purpose β-thalassemia major (β-TM) is an autosomal recessive disorder caused by mutations in the β-globin gene of hemoglobin. The disease is characterized by splenomegaly due to ineffective erythropoiesis, iron accumulation signs in tissues as a result of increased iron absorption, bone expansion due to increased erythropoietic activity, and decreased tissue oxygenation. One of the effected organ can be the lungs due to excessive iron deposition in these patients. The current study aimed to investigate the effect of serum ferritin level, which is known as a marker of iron accumulation in tissues, on pulmonary function tests (PFT) in patients with β-TM. Methods and Materials Patients aged ≥6 years who were regularly followed in the pediatric hematology section of Mersin City Research and Training Hospital with a diagnosis of β-TM were included. All patients received regular blood transfusion and iron chelation therapy. Study participants underwent PFT prior to blood transfusion in the pediatric pulmonology section Results A total of 43 patients with β-TM were studied. Included patients were divided into two groups according to the mean annual ferritin level; low ferritin group if below 2000 ml/ng and high ferritin group if above 2000 ml/ng. The low ferritin group was consisted of 19 patients and the high ferritin group was consisted of 24 patients. The characteristics of these two groups are shown in Table 1. There were no statistical significance in age, gender, body mass index, age at diagnosis, mean annual hemoglobin, splenectomy, cardiac involvement and oxygen saturation among both groups, but the number of annual transfusion was significantly higher in the high ferritin group than lower ferritin group. When PFT parameters of both groups were compared, FVC (forced vital capacity) was statistically lower in the high ferritin group compared to the low ferritin group. Other parameters included FEV 1 (forced expiratory volume in 1 second), FEV 1/FVC ratio, PEF (peak expiratory flow) and FEF 25-75 (forced expiratory flow between 25% and 75% of vital capacity) were similar among groups. (Table 2) Discussion Patients with β-TM may accumulate iron in the interstitial area of the lungs which can lead fibrosis and impaired lung function over time. There are several studies investigated lung dysfunction and its etiology in these patients. Although the results of the studies are varied, the majority of them reported a restrictive pattern of respiratory dysfunction in thalassemia patients. Additionally, some studies showed the presence of mild or moderate obstruction in small airways and decrease in diffusion capacity with the increase of alveolar-capillary membrane thickness at advanced ages. In the present study, we found that patients with β-TM who had high ferritin level showed restrictive type lung function compared to those with low ferritin level. There were no difference among the groups in obstructive parameters (i.e. FEV 1, FEV 1/FVC, FEF 25-75) of PFT. In the literature, studies investigating PFT in patients with high ferritin levels had variable results, impaired or no change, in pulmonary status. In conclusion, loss of respiratory function and impaired tissue oxygenation in patients with β-TM may develop over time due to iron deposition in the interstitial area. PFT assessment of these patients is essential and recommended for the detection of early lung disease. Routine PFT follow in patients with β-TM of high ferritin values is highly important.

189 Omega-6 pathway switch associated with neutrophil influx and structural damage and represents a distinct disease stage independent of age in early cystic fibrosis lung disease

189 Omega-6 pathway switch associated with neutrophil influx and structural damage and represents a distinct disease stage independent of age in early cystic fibrosis lung disease

139 Comprehension of early cystic fibrosis lung disease or howto TRACK-CF

139 Comprehension of early cystic fibrosis lung disease or howto TRACK-CF

112 The lung clearance index to inform clinical decision-making in early cystic fibrosis lung disease: findings from a prospective study

112 The lung clearance index to inform clinical decision-making in early cystic fibrosis lung disease: findings from a prospective study

Pulmonary exacerbations in early cystic fibrosis lung disease are marked by strong modulation of CD3 and PD-1 on luminal T cells.

In chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process, remain unknown. Children with CF aged 0-5 years were enrolled in a longitudinal, single-center cohort study. Blood (n = 35) and bronchoalveolar lavage (BAL) fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into (i) no prior PE, (ii) past history of PE prior to stable visit, or (iii) current PE. PEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL, and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend toward an increased frequency of hyperexocytic "GRIM" neutrophils, which we previously identified in chronic CF. Interestingly, expression levels of the T-cell receptor associated molecule CD3 and of the inhibitory programmed death-1 (PD-1) receptor were respectively decreased and increased on T cells from BAL compared to blood in all patients. When categorized by PE status, CD3 and PD-1 expression on blood T cells did not differ among patients, while CD3 expression was decreased, and PD-1 expression was increased on BAL T cells from patients with current PE. Our findings suggest that airway T cells are engaged during early-life PEs, prior to the onset of chronic neutrophilic inflammation in CF. In addition, increased blood neutrophil frequency and a trend toward increased BAL frequency of hyperexocytic neutrophils suggest that childhood PEs may progressively shift the balance of CF airway immunity towards neutrophil dominance.

Clinical improvement in early onset interstitial lung disease using rituximab in children with anti-MDA5 positive juvenile dermatomyositis.

Children with juvenile dermatomyositis (JDM) and antibodies to melanoma differentiation associated gene 5 (anti-MDA5) are at increased risk of severe disease complications, including interstitial lung disease (ILD). Data regarding treatment of disease complications in this patient population is limited. In this study, we examined the disease course of children with JDM and anti-MDA5 antibodies before and after treatment with rituximab (RTX). Patients (age 2-21 years) seen at the Children's Hospital at Montefiore between July 2012 and August 2021, with a diagnosis of JDM, positive anti-MDA5 positive antibodies, evidence of ILD, and who were treated with rituximab were eligible for inclusion. Retrospective clinical and laboratory data were reviewed. Five out of 8 patients with positive anti-MDA5 antibodies had evidence of ILD (62.5%). Four patients had data available for review. All patients received at least 5 courses of RTX infusions, with discontinuation of steroids by an average of 12 months after starting RTX and a decrease to fewer than two concurrent medications by fifth course of RTX. Indicators of ILD on high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) either improved or fully resolved over the course of RTX treatment for all patients. Patients also demonstrated resolution of active cutaneous manifestations and musculoskeletal disease activity. This is the first study to examine the use of RTX in children with JDM and anti-MDA5 antibodies, with notable improvements ILD, cutaneous and musculoskeletal manifestations. Further studies are needed to better understand the efficacy of RTX on JDM disease related complications.

Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease.

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n=27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.

Pulmonary Function Tests in the Evaluation of Early Lung Disease in Cystic Fibrosis.

Properly evaluating respiratory system dysfunction is essential in children with cystic fibrosis (CF). This prospective study aimed to assess the course of early lung disease based on multiple breath nitrogen washout (MBNW), impulse oscillometry (IOS), and conventional techniques, such as spirometry and body plethysmography. Over a 2 year recruitment period, subjects with CF aged 7-18 performed pulmonary function tests (PFTs). Moreover, the nutritional and microbiological status, frequency of pulmonary exacerbations (PExs), and patients' health-related quality of life (HRQoL) were assessed. The mean age of the children (n = 69) was 14.09 ± 3.26 years; F/M 37/32. Spirometry-based diagnoses of normal lung function (forced expiratory volume in 1 s, FEV1 ≥ 90%pred), mild (FEV1 70-89%pred) and moderate (FEV1 40-69%pred) lung diseases were established in 34 (49.3%), 25 (36.2%), and 10 (14.5%) patients, respectively. An elevated lung clearance index (LCI > 6.98) was observed in 85% of the subjects with normal FEV1. The presence of Pseudomonas aeruginosa infection (n = 16) and the number of PExs treated with IV antibiotics were associated with significantly worse PFT results. MBNW and IOS are more helpful tools than conventional techniques in assessing early lung disease in CF. LCI is a more useful parameter for detecting functional abnormalities than FEV1 in school-age children.