Hypersensitivity pneumonitis (HP) is an immunologically mediated form of lung disease resulting from inhalational exposure to any of a large variety of antigens. A subgroup of patients with HP develops pulmonary fibrosis (fibrotic HP; FHP), a significant cause of morbidity and mortality. This study will evaluate the safety and efficacy of the antifibrotic pirfenidone in treating FHP. This single-centre, randomised, double-blind, placebo-controlled trial is enrolling adults with FHP (ClinicalTrials.gov: NCT02958917). Study participants must have fibrotic abnormalities involving ≥5% of the lung parenchyma on high-resolution computed tomography scan, forced vital capacity (FVC) ≥40% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised in a 2:1 ratio to receive pirfenidone 2403 mg·day-1 or placebo. The primary efficacy end-point is the mean change in FVC % predicted from baseline to week 52. A number of secondary end-points have been chosen to evaluate the safety and efficacy in different domains.

Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide (D LCO). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to D LCO for patients treated with ELVR.

Sarcoidosis is a multisystemic granulomatous disease with still unknown etiology. Our previous studies showed a significantly higher percentage of CD34 + cells in the peripheral blood in patients with sarcoidosis (SA) compared to the control group. The objective of the present study was to characterized of the CD34 + cell population in peripheral blood in patients with SA with reference to the control group. Moreover in patients with SA, fibrocytes and endothelial cells were analysed and their relationship to the fibrosis process based on assessment of diffusing capacity for carbon monoxide (DLCO).

In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

Introduction It is hypothesized that bronchoalveolar lavage (BAL) neutrophilia, Krebs von den Lungen-6 (KL-6), and C-reactive protein (CRP) predict the severity of chronic fibrosing interstitial lung diseases (CF-ILDs). Methods This cross-sectional study enrolled 30 CF-ILD patients. Using Pearson's correlation analysis, BAL neutrophils, KL-6, and CRP were correlated with forced vital capacity (FVC), diffusing lung capacity for carbon monoxide (DLCO), six-minute walk distance (6MWD), partial pressure of oxygen (PaO2), computed tomography fibrosis score (CTFS), and pulmonary artery systolic pressure (PASP). Using the receiver operator characteristic (ROC) curve, BAL KL-6 and CRP were evaluated against FVC% and DLCO% in isolation and combination with BAL neutrophilia for predicting the severity of CF-ILDs. Results BAL neutrophilia significantly correlated only with FVC% (r = -0.38, P = 0.04) and DLCO% (r = -0.43, P = 0.03). BAL KL-6 showed a good correlation with FVC% (r = -0.44, P < 0.05) and DLCO% (r = -0.50, P = 0.02), while BAL CRP poorly correlated with all parameters (r = 0.0-0.2). Subset analysis of BAL CRP in patients with CTFS ≤ 15 showed a better association with FVC% (r = -0.28, P = 0.05) and DLCO% (r = -0.36, P = 0.04). BAL KL-6 cut-off ≥ 72.32 U/ml and BAL CRP ≥ 14.55 mg/L predicted severe disease with area under the curve (AUC) values of 0.77 and 0.71, respectively. The combination of BAL neutrophilia, KL-6, and CRP predicted severity with an AUC value of 0.89. Conclusion The combination of BAL neutrophilia, KL-6, and CRP facilitates the severity stratification of CF-ILDs complementing existing severity parameters.

The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial.

Purpose: The aim of this study was to evaluate the role of Pi10 in patients with fibrotic interstitial lung abnormality (fibrotic ILA) in a chest CT, according to cumulative cigarette smoking. Methods: We retrospectively assessed 54 fibrotic ILA patients and 18 healthy non-smokers (control) who underwent non-enhanced CT and pulmonary function tests. We quantitatively analyzed airway changes (the inner luminal area, airway inner parameter, airway wall thickness, Pi10, skewness, and kurtosis) in the chest CT of fibrotic ILA patients, and the fibrotic ILA patients were categorized into groups based on pack-years: light, moderate, heavy. Airway change data and pulmonary function tests among the three groups of fibrotic ILA patients were compared with those of the control group by one-way ANOVA. Results: Mean skewness (2.58 ± 0.36) and kurtosis (7.64 ± 2.36) in the control group were significantly different from those of the fibrotic ILA patients (1.89 ± 0.37 and 3.62 ± 1.70, respectively, p < 0.001). In fibrotic ILA group, only heavy smokers had significantly increased Pi10 (mean increase 0.04, p = 0.013), increased airway wall thickness of the segmental bronchi (mean increase 0.06 mm, p = 0.005), and decreased lung diffusing capacity for carbon monoxide (p = 0.023). Conclusion: Pi10, as a biomaker of quantitative CT in fibrotic ILA patients, can reveal that smoking affects airway remodeling.

HIV infection is associated with impaired lung gas transfer as indicated by a low diffusing capacity (DLCO), but the mechanisms are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system-wide perturbations that could be reflected by alterations in peripheral blood leukocyte (PBL) gene expression. Forty HIV-infected (HIV(+)) and uninfected (HIV(-)) men with preserved versus low DLCO were enrolled. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from PBLs and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV(+) versus HIV(-) subjects with preserved DLCO and those with low DLCO to identify differentially activated pathways. Using pathway-based analyses, we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. Applying a similar analysis to subjects with low DLCO, we identified a much broader repertoire of pro-inflammatory and immune-related pathways in HIV(+) patients relative to HIV(-) subjects, with up-regulation of multiple interleukin pathways, interferon signaling, and toll-like receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV(+) patients with low DLCO relative to the other groups. Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated gas exchange impairment.

Fifty-six patients with kryptogenic fibrosing alveolitis were followed up during 6.3 years (from 1.5 to 19.3 years) after their first functional examination including cardiac catheterization. Twenty-two out of 56 patients died during the follow-up. The significance of individual functional tests as predictors of the survival was evaluated by means of actuarial survival probability curves. Four variables were predictive for nonsurvival: a mean pulmonary arterial pressure exceeding 30 mmHg, a vital capacity of 60% of the predicted value or lower, a CO diffusing capacity at rest less than 40% of the predicted value, an age at first symptoms over 30 years. Other variables were not significantly predictive for a given time of follow-up. A simple prognostic score derived from predictive variables was able to separate the subgroup of patients with unfavourable short-term prognosis. Among significantly predictive variables, a resting pulmonary arterial pressure over 30 mmHg appears to be the most important.

Tidal volume at peak exercise and vital capacity ratio (VTpeak/VC) and VTpeak/inspiratory capacity (IC) were used to differentiate lung expansion in subjects with normal health and chronic obstructive pulmonary disease (COPD) from that in subjects with restrictive ventilation. However, VC and IC variably change due to pseudorestriction of lung volumes. Thus, these variables are currently not recommended. In contrast, total lung capacity (TLC) does little change during exercise. The aims of the study investigated whether VTpeak/TLC is more significantly correlated with static air trapping and lung hyperinflation in patients with COPD than VTpeak/IC, VTpeak/FVC, and VTpeak/SVC (study 1), and developed a marker to replace dynamic IC maneuvers by evaluation of the relationship between end-expiratory lung volume (EELV) and VTpeak/TLC and identification of a cutoff value for VTpeak/TLC (study 2). One hundred adults with COPD (study 1) and 23 with COPD and 19 controls (study 2) were analyzed. Spirometry, lung volume, diffusing capacity, incremental cardiopulmonary exercise tests with dynamic IC maneuvers were compared between groups. An ROC curve was generated to identify a cut off value for VTpeak/TLC. In study 1, VTpeak/TLC was more significantly associated with airflow obstruction, static air trapping and hyperinflation. In study 2, VTpeak/TLC was highly correlated with EELV in the patients (r = -0.83), and VTpeak/TLC ≥ 0.27 predicted that 18% of the patients with static air trapping and hyperinflation can expand their VT equivalent to the controls. In conclusions, VTpeak/TLC was superior to other VTpeak/capacities. VTpeak/TLC may be a marker of dynamic hyperinflation in subjects with COPD, thereby avoiding the need for dynamic IC maneuvers. VTpeak/TLC < 0.27 identified approximately 82% of subjects with COPD who could not adequately expand their tidal volume. As most of our participants were male, further studies are required to elucidate whether the results of this study can be applied to female patients with COPD.

Heart failure (HF) is a chronic condition in which the heart does not pump enough blood to meet the body's demands. Diffusing capacity of the lung for nitric oxide (DLNO) and carbon monoxide (DLCO) may be used to classify patients with HF, as DLNO and DLCO are lung function measurements that reflect pulmonary gas exchange. Our objectives were to determine 1) if DLNO added to DLCO testing predicts HF better than DLCO alone and 2) whether the binary classification of HF is better when DLNO z-scores are combined with DLCO z-scores than using DLCO z-scores alone.

The sequelae of COVID-19 have been described as a multisystemic condition, with a great impact on the cardiovascular and pulmonary systems with abnormalities in pulmonary function tests, such as lower diffusing capacity of the lung for carbon monoxide (DLco) levels and pathological patterns in spirometry; persistence of radiological lesions; cardiac involvement such as myocarditis and pericarditis; and an increase in mental disorders such as anxiety and depression. Several factors, such as infection severity during the acute phase as well as vaccination status, have shown some variable effects on these post-COVID-19 conditions, mainly at a clinical level such as symptoms persistence. Longitudinal assessments and reversibility of changes across the spectrum of disease severity are required to understand the long-term impact of COVID-19.

Rationale. Matrix metalloproteinase-9 (MMP-9) expression is upregulated in alveolar macrophages (AM) of HIV1(+) smokers who develop emphysema. Knowing that lung epithelial lining fluid (ELF) of HIV1(+) smokers contains increased levels of inflammatory cytokines compared to HIV1(-) smokers, we hypothesized that upregulation of lung cytokines in HIV1(+) smokers may be functionally related to increased MMP-9 expression. Methods. Cytokine arrays evaluated cytokine protein levels in ELF obtained from 5 groups of individuals: HIV1(-) healthy nonsmokers, HIV1(-) healthy smokers, HIV1(-) smokers with low diffusing capacity (DLCO), HIV1(+) nonsmokers, and HIV1(+) smokers with low DLCO. Results. Increased levels of the Th17 related cytokine IL-23 were found in HIV1(-) smokers with low DLCO and HIV1(+) smokers and nonsmokers. Relative IL-23 gene expression was increased in AM of HIV1(+) individuals, with greater expression in AM of HIV1(+) smokers with low DLCO. Infection with HIV1 in vitro induced IL-23 expression in normal AM. IL-23 stimulation of AM/lymphocyte cocultures in vitro induced upregulation of MMP-9. Lung T lymphocytes express receptor IL-23R and interact with AM in order to upregulate MMP-9. Conclusion. This mechanism may contribute to the increased tissue destruction in the lungs of HIV1(+) smokers and suggests that Th17 related inflammation may play a role.

BACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.

By evaluating S100 calcium binding protein A9 (S100A9) and Klebs von den Lungen-6 (KL-6) expression in patients with 4 common interstitial lung diseases (ILDs), we aimed to investigate whether S100A9 or KL-6 can be of any value in the differential diagnosis of these ILDs and simultaneously signal the disease progression.We collected the data of patients diagnosed with the 4 ILDs and underwent fiber-optic bronchoscopy and BAL in the First Affiliated Hospital, China Medical University from January 2012 to December 2020. The data related to BGA, C-reactive protein, pulmonary function test, total number and fraction of cells, T lymphocyte subsets in bronchoalveolar lavage fluid (BALF), and the expression of S100A9 and KL-6 in BALF and serum were collected. We analyzed, whether S100A9 or KL-6 could serve as a biomarker for differential diagnosis between the 4 common ILDs; whether the levels of S100A9 and KL-6 correlated with each other; whether they were correlated with other clinical parameters and disease severity.This study included 98 patients, 37 patients with idiopathic pulmonary fibrosis (IPF), 12 with hypersensitivity pneumonitis, 13 with connective tissue disease-associated ILD, and 36 with sarcoidosis (SAR): stage I (18), stage II (9), stage III (5), and stage IV (4). The expression of KL-6 in BALF was significantly higher in IPF patients than other 3 groups (all P-value < .05). However, there was no significant difference in the levels of S100A9 in BALF and serum between the 4 groups (P-value > .05). The levels of S100A9 in BALF of IPF patients was positively and significantly correlated with KL-6 expression and the percentage of neutrophils in BALF (P-value < .05). Along with the stage increase of SAR patients, the level of S100A9 in BALF gradually increased, which was negatively and significantly correlated with the forced vital capacity/predicted, carbon monoxide diffusing capacity/predicted%, and PaO2 (all P-value < .05).The expression of KL-6 in BALF can be used as a biomarker to differentiate IPF from the other 3 common ILDs. While, this was not the case with expression of S100A9 in BALF and serum. However, the expression S100A9 in BALF is useful to indicate the progression of SAR. Thus, simultaneous measurement of KL-6 and S100A9 levels in BALF makes more sense in differential diagnosing of the 4 common ILDS.

Sickle cell anemia (SCA) causes dysfunction of multiple organs, with pulmonary involvement as a major cause of mortality. Recently, there has been growing interest in the nitrogen single-breath washout (N2SBW) test, which is able to detect ventilation heterogeneity and small airway disease when the results of other pulmonary function tests (PFTs) are still normal. Thus, the objectives of the present study were to assess the heterogeneity in the ventilation distribution in adults with SCA and to determine the association between the ventilation distribution and the clinical, cardiovascular, and radiological findings. This cross-sectional study included 38 adults with SCA who underwent PFTs, echocardiography, computed tomography (CT), and 6-min walk test. To evaluate the ventilation heterogeneity, the patients were categorized according to the phase III slope of the N2SBW (SIIIN2). Compared with adults with lower SIIIN2 values, adults with higher SIIIN2 values showed lower hemoglobin levels (P=0.048), a history of acute chest syndrome (P=0.001), an elevated tricuspid regurgitation velocity (P=0.039), predominance of a reticular pattern in the CT (P=0.002), a shorter 6-min walking distance (6MWD) (P=0.002), and lower peripheral oxygen saturation (SpO2) after exercise (P=0.03). SIIIN2 values correlated significantly with hemoglobin (rs=-0.344; P=0.034), forced vital capacity (rs=-0.671; P<0.0001), diffusing capacity for carbon monoxide (rs=-0.376; P=0.019), 6MWD (rs=-0.554; P=0.0003), and SpO2 after exercise (P=0.040). Heterogeneity in the ventilation distribution is one of the most common pulmonary dysfunctions in adults with SCA. Moreover, relationships exist between ventilation heterogeneity, worsening of pulmonary structural damage, and reduced tolerance for exercise.

Objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable and different from continuously progressive idiopathic pulmonary fibrosis (IPF). Most proposed definitions of progressive pulmonary fibrosis or SSc-ILD severity are based on the research data from patients with IPF and are not validated for patients with SSc-ILD. Our study aimed to gather the current evidence for severity, progression and outcomes of SSc-ILD.Methods A systematic literature review to search for definitions of severity, progression and outcomes recorded for SSc-ILD was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in Medline, Embase, Web of Science and Cochrane Library up to 1 August 2023.Results A total of 9054 papers were reviewed and 342 were finally included. The most frequent tools used for the definition of SSc-ILD progression and severity were combined changes of carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC), isolated FVC or DLCO changes, high-resolution CT (HRCT) extension and composite algorithms including pulmonary function test, clinical signs and HRCT data. Mortality was the most frequently reported long-term event, both from all causes or ILD related.Conclusions The studies presenting definitions of SSc-ILD 'progression', 'severity' and 'outcome' show a large heterogeneity. These results emphasise the need for developing a standardised, consensus definition of severe SSc-ILD, to link a disease specific definition of progression as a surrogate outcome for clinical trials and clinical practice.PROSPERO registration number CRD42022379254.Cite Now.

The aim of this work was to verify the correlations between different pulmonary morphological patterns and functional outcomes in sarcoidosis patients, using a validated score for the comparison between the high-resolution computed tomography (HRCT) of patients belonging to different imaging patterns. From the electronic database of the reference center for interstitial lung diseases of our University Hospital, we retrospectively selected 55 patients with a diagnosis of sarcoidosis according to the American Thoracic Society (ATS) criteria; we evaluated the initial HRCT examination and pulmonary function tests collected at baseline and after a year. Patients were divided into typical (48% of patients) and atypical (52%) HRCT patterns, and a computer tomography activity score (CTAS) was associated with each HRCT appearance detected; clinical history, impact of therapy, and extra-thoracic locations were also considered. We found that worsening of diffusing capacity for carbon monoxide (DLCO) is related to the CTAS (r = -0.20, p = 0.01), and there was an inverse correlation between the variation of forced vital capacity (FVC) and the value of the CTAS (r = -0.30, p = 0.23) in the subgroup of patients with atypical patterns. CTAS were higher in patients with extra-pulmonary localizations (p = 0.05) and the subgroup of patients with extra-thoracic locations and atypical manifestations had a greater worsening in terms of variation of FVC (p = 0.03) and DLCO% (p = 0.04). No difference between treated and untreated patients was found.

The distribution of lung disease induced by inhaled cigarette smoke is complex, depending on many factors. With the knowledge that the small airway epithelium (SAE) is the earliest site of smoking-induced lung disease, and that the SAE gene expression is likely sensitive to inhaled cigarette smoke, we compared upper vs. lower lobe gene expression in the SAE within the same cigarette smokers to determine if the gene expression patterns were similar or different. Active smokers (n = 11) with early evidence of smoking-induced lung disease (normal spirometry but low diffusing capacity) underwent bronchoscopy and brushing of the upper and lower lobe SAE in order to compare upper vs lower lobe genome-wide and smoking-responsive gene expression by microarray. Cluster and principal component analysis demonstrated that, for each individual, the expression of the known SAE smoking-responsive genes were highly correlated in upper and lower lobe pairs, although, as expected, there were differences in the smoking-induced changes in gene expression from individual to individual. These observations support the concept that the heterogeneity observed among smokers in the anatomic distribution of smoking-induced disease are not secondary to the topographic differences in the effects of cigarette smoke on the airway epithelium.

We aimed to investigate changes in pulmonary function and computed tomography (CT) findings in patients with coronavirus disease 2019 (COVID-19) during the recovery period. COVID-19 patients underwent symptom assessment, pulmonary function tests, and high-resolution chest CT 6 months after discharge from the hospital. Of the 54 patients enrolled, 31 and 23 were in the moderate and severe group, respectively. The main symptoms 6 months after discharge were fatigue and exertional dyspnea, experienced by 24.1% and 18.5% of patients, respectively, followed by smell and taste dysfunction (9.3%) and cough (5.6%). One patient dropped out of the pulmonary function tests. Of the remaining 54 patients, 41.5% had pulmonary dysfunction. Specifically, 7.5% presented with restrictive ventilatory dysfunction (forced vital capacity <80% of the predicted value), 18.9% presented with small airway dysfunction, and 32.1% presented with pulmonary diffusion impairment (diffusing capacity for carbon monoxide <80% of the predicted value). Of the 54 patients enrolled, six patients dropped out of the chest CT tests. Eleven of the remaining 48 patients presented with abnormal lung CT findings 6 months after discharge. Patients with residual lung lesions were more common in the severe group (52.6%) than in the moderate group (3.4%); a higher proportion of patients had involvement of both lungs (42.1% vs. 3.4%) in the severe group. The residual lung lesions were mainly ground-glass opacities (20.8%) and linear opacities (14.6%). Semiquantitative visual scoring of the CT findings revealed significantly higher scores in the left, right, and both lungs in the severe group than in the moderate group. COVID-19 patients 6 months after discharge mostly presented with fatigue and exertional dyspnea, and their pulmonary dysfunction was mostly characterized by pulmonary diffusion impairment. As revealed by chest CT, the severe group had a higher prevalence of residual lesions than the moderate group, and the residual lesions mostly manifested as ground-glass opacities and linear opacities.