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Abstract Chronic lung allograft dysfunction (CLAD) remains a leading cause of death after lung transplantation. KL-6 is a reliable biomarker for various interstitial lung diseases and levels are increased in lung transplant recipients with versus without bronchiolitis obliterans syndrome. This study investigated whether changes in serum KL-6 levels over time were associated with CLAD. Twenty-one lung transplant recipients had serum KL-6 measured (NANOPIA®) at baseline and after 7 years. Changes in serum KL-6 levels from baseline were determined. Receiver operating characteristic curves and Kaplan-Meier analysis were used to test the predictive value of changes in serum KL-6 over time. The average increase in KL-6 in patients with CLAD was 15% versus a 28% decrease in non-CLAD patients (p =.042). An 11% decrease in serum KL-6 level was determined as the best cut-off value to be associated with the development of CLAD (86% sensitivity, 78% specificity). Kaplan-Meier analysis confirmed the association between this cut-off and the development of CLAD (log rank p =.013). In this small cohort, changes in serum KL-6 over time were associated with the development of CLAD after lung transplantation. Highlights • KL-6 is known to be a sensitive biomarker for various interstitial lung diseases. • Chronic lung allograft dysfunction (CLAD) can develop after lung transplant. • KL-6 levels increased or were stable after transplant in those who developed CLAD. • KL-6 levels decreased over time in those who did not develop CLAD. • Change in KL-6 over time might be a biomarker for the development of CLAD. [ABSTRACT FROM AUTHOR]

Background and objectives: Pulmonary alveolar proteinosis (PAP) is characterized by alveolar accumulation of surfactant lipoproteins. Proteasomes are involved in the nonlysosomal protein degradation. We hypothesize that enzymatically active proteasome is increased in the alveolar space of PAP. Patients and methods: 31 PAP patients (29 with primary, 2 with secondary form), 14 disease controls (10 with COPD and 4 with emphysema) and 18 healthy controls were studied. 20S Proteasome was measured by ELISA in bronchoalveolar lavage fluid (BALF) and in serum. Enzyme activity of extracellular proteasome (pkat/mg) was measured through fluorogenic substrate cleavage. Results: Proteasome concentration in BAL was higher in PAP patients than in disease controls or healthy subjects (566 ± 420 vs 53 ± 27 vs 60 ± 42 ng/ml, respectively, p < 0.0001 for both). Serum proteasome levels were higher in PAP patients than in healthy controls (825 ± 712 vs 405 ± 176 ng/ml, p = 0.018). PAP patients with active disease had higher serum levels than those who achieved remission (1317 ± 1176 vs 439 ± 422 ng/ml, p = 0.008). Proteasomal enzyme activity was increased in BAL of PAP patients (p < 0.05). Conclusions: The 20S proteasome is increased and active in BAL of patients with PAP. Extracellular proteasome may contribute to the alveolar degradation of accumulated proteins in PAP. [ABSTRACT FROM AUTHOR]

Objectives: A few studies on small patient series have investigated the relationship between gastroesophageal reflux and bronchial responsiveness as expressed by exercise-induced bronchoconstriction (EIB) with non-conclusive results. The aim of this study was to evaluate whether the presence of acid in the oesophagus may influence EIB. Methods: 45 patients with bronchial asthma underwent spirometry, exercise challenge on bicycle ergometer and 24 h oesophageal pH monitoring. Subjects with EIB (Forced expiratory volume in the first second (FEV1)) percentage decrease after exercise (ΔFEV1) ⩾15%, n = 28) were retested after a 2 week treatment course with omeprazole 40 mg/daily. Exercise at baseline was performed at the same time as oesophageal pH monitoring. Results: In basal condition, there was no difference in FEV1 acid exposure time or number of refluxes measured during 24 h pH monitoring between patients with and without EIB. There was no relationship between spirometry results and ΔFEV1 on one hand, and parameters of gastroesophageal reflux on the other. Nine patients with EIB (31.0%) and six patients without EIB (37.5%) had one or more episodes of GER during exercise challenge, without significant differences between the two groups. After gastric acid inhibition by omeprazole, ΔFEV1 did not change significantly. Conclusions: The results indicate that acid in the oesophagus, or its short-term inhibition by proton pump inhibitors, has no influence on exercise-induced bronchoconstriction. [ABSTRACT FROM AUTHOR]

Introduction: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a standard procedure in cases of enlarged mediastinal lymph nodes. Recently, new tools were developed aiming to improve the diagnostic yield. A novel crown-cut needle is considered to obtain tissue cores which can be beneficial for the evaluation by the pathologist. This study aimed to compare the novel 22G crown-cut needle with a conventional 22G needle with EBUS guidance in the diagnosis of sarcoidosis. Methods: We designed a single-center prospective randomized clinical trial between March 2020 and January 2021 with 30 patients with mediastinal lymphadenopathy and suspected sarcoidosis. Results: 24 patients (mean age 49.5 vs 54.1, mean FVC 73.7% vs 86.7%, mean DLCO 72.4% vs 72.5% for crown-cut needle vs conventional needle, respectively) were diagnosed with sarcoidosis. In the remaining six patients, sarcoidosis was reasonably excluded. The diagnostic yield for sarcoidosis was 77% with the crown-cut needle vs. 82% with the conventional needle (p > 0.05). In patients with histopathologic hallmarks typical of sarcoidosis (n = 19), the crown-cut needle was superior in detecting granulomas (8.3 vs 3.8 per cytoblock, p < 0.05) and histiocytes (502 vs 186 per cytoblock, p < 0.05). Four of seven bronchoscopists experienced difficulties passing through the bronchial wall with the crown-cut needle and one episode of bleeding occurred in this group which made interventions necessary. Conclusions: Despite equivalence in diagnostic accuracy, the crown-cut needle was superior to the conventional needle in detecting granulomas and histiocytes. This indicates greater potential for obtaining higher quality sample material with the crown-cut needle in cases of granulomatous inflammation. [ABSTRACT FROM AUTHOR]

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.Methods: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24.Results: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.Conclusions: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.). [ABSTRACT FROM AUTHOR]

Purpose: The clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. Hence, sarcoidosis patients may suffer from a great variety of symptoms. The aim of this study was to compare the self-reported burden of sarcoidosis patients in Denmark, Germany and the Netherlands, especially the prevalence of fatigue and small fiber neuropathy (SFN)-related symptoms, as well as differences in treatment strategies. Methods: A cross-sectional web-based anonymous survey about complaints was conducted among sarcoidosis patients. Patients were invited to take part through the sarcoidosis patient societies as well as through outpatient sarcoidosis clinics in these countries. Results: The questionnaire was completed by 1072 sarcoidosis patients (152 Danish, 532 German and 388 Dutch). Almost all patients reported having sarcoidosis-associated symptoms (organ-related as well as non-specific, non-organ related). Fatigue was reported by almost all respondents (90%), followed by pulmonary symptoms (72.4%). More than 50% of the respondents were being treated with prednisone, which was comparable in all three countries. In contrast, second- and third-line treatment differed substantially between Denmark, Germany and the Netherlands. Conclusion: Sarcoidosis patients in Denmark, Germany and the Netherlands present with similar self-reported symptoms, organ-related as well as non-specific, non-organ related. Fatigue (90%) and symptoms associated with SFN (86%) were highly prevalent in all three countries. [ABSTRACT FROM AUTHOR]

A 51-year-old active smoker with primary acquired pulmonary alveolar proteinosis (PAP) diagnosed by biopsy and anti-GM-CSF antibodies was treated safely with whole-lung lavage (WLL). This resulted in a rapid improvement of symptoms and arterial blood oxygenation, but not of standard lung function parameters. However, we also performed the multiple-breath nitrogen washout (MBW) test to determine the lung clearance index (LCI) as well as indices of acinar ventilation heterogeneity (Sacin) and conductive ventilation heterogeneity (Scond). At baseline, a distinct abnormality was seen for Sacin and LCI, while Scond was at the upper limit of normal for this subject. Sacin, in particular, was in excess of the Sacin abnormality corresponding to a 20-pack-year smoking history. Immediately after WLL, Sacin and Scond both fell to within a normal range while LCI also decreased but remained abnormal. The Sacin decrease was much greater than the Scond decrease, which was to be expected after 1 week of smoking cessation at the hospital (smoking was resumed after release from hospital). A follow-up visit 7 weeks after WLL revealed a spectacular improvement on CT scan and improvements in standard lung function. Another follow-up visit 14 weeks after WLL showed further improvements in standard lung function, and both Sacin and Scond remained well within the normal range, and LCI was above the upper limit of normal. We conclude that in this patient, removal of excess surfactant by WLL resulted in a restored ventilation distribution in most of the distal air spaces. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The long-term survival of lung transplant recipients is significantly limited by the occurrence of chronic lung allograft dysfunction (CLAD). A single nucleotide polymorphism (SNP) in the promoter region of the MUC5B-gene (rs35705950) has been identified as an independent risk factor for the development of idiopathic pulmonary fibrosis (IPF). Moreover, MUC5B genotype is associated with survival in IPF patients. Aim of the study was to investigate whether the development of CLAD is associated with genotype in MUC5B-promoter polymorphism. 73 patients, who underwent lung transplantation from 1998 to 2015 for several indications, and 50 healthy controls were retrospectively studied. CLAD was defined as persistent decline of FEV 1 to < 80 % of the post-transplant baseline. MUC5B rs35705950 SNP genotype was detected by real time PCR and pyrosequencing. During the follow-up period of 8 ± 4 years, 51 % of patients developed CLAD. MUC5B rs35705950 alleles were in Hardy-Weinberg equilibrium and genotype distribution did not differ between healthy controls and transplant recipients. 53 % of the patients carrying the GG genotype and 40 % of the patients carrying the GT genotype group developed CLAD (p=0.398). No correlation between MUC5B rs35705950 genotype and age, gender, lung function tests and survival was found. In our cohort, genotype in the MUC5B-promoter polymorphism was not associated with the development of CLAD or survival. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained a mistake in coauthor's given name. The abbreviated given name "M.D." for coauthor M.D.P. Elfferich's name has been inadvertently deleted during the production process. [ABSTRACT FROM AUTHOR]