SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.

The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.

Lung cancer in patients with idiopathic pulmonary fibrosis: A retrospective multicentre study in Europe.

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/µl than patients with monocyte count ≥0.95 K/µl (HR [<0.60 vs. ≥0.95 K/µl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/µl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02). CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

How Informed Are German Patients with Pulmonary Sarcoidosis about Their Disease?

BACKGROUND: Sarcoidosis is a multisystemic disease with a heterogenous course of disease. Comprehensive information about the complexity and treatment indications is essential for improving patient knowledge and adhering to therapy. OBJECTIVES: The aim of our study was to investigate the level and resources of information in patients with sarcoidosis and to analyze differences in patient subgroups including age and gender. METHODS: We conducted a questionnaire-based online survey in Germany and three semi-structured focus group interviews. The interviews were evaluated independently by two investigators using a structured qualitative content analysis. RESULTS: A total of 402 completed questionnaires were analyzed, 65.8% of participants were women, and the mean age was 53 years. The majority of patients felt well informed about their disease in general (59.4%), but 40.6% were inadequately informed. The most relevant information gaps related to the future perspective (70.6%) as well as fatigue and diffuse pain (63.9%). Most patients received information from their treating pulmonologist (72.1%). 94% used the internet, especially homepages of patient support groups (75.2%). Male participants more often reported being well informed about their disease and were more satisfied with the information (p = 0.001). During the interviews, patients expressed their wish for more comprehensive information and highlighted the importance of psychological co-care as well as the future perspective. CONCLUSIONS: A relevant proportion of patients with sarcoidosis are inadequately informed about their own disease, particularly with regard to factors impeding quality of life such as fatigue. Efforts are needed to improve the level and quality of information.

Severe tracheal tear - an alternative extracorporeal membrane oxygenation indication.

INTRODUCTION: Conservative management is usually preferred for iatrogenic tracheal injuries. Venovenous extracorporeal membrane oxygenation (V-V ECMO) is mostly used in acute refractory hypoxemia, airway lesions are an alternative indication. CASE REPORT: A 51-year-old female was transferred with a large tracheal tear after plastic tracheotomy. Due to a critical ventilation situation with hypercapnia, conservative management was set and V-V ECMO was installed. With optimized tube positioning, minimal ventilation and gas transfer via V-V ECMO, a complete healing of the injury could be achieved. DISCUSSION: Fast diagnosis of tracheal injuries is essential; transfer to a specialized centre should be considered. In our case, organ support via ECMO was necessary due to a difficult ventilation situation with persisting hypercapnia. Thus, reduction in ventilation pressures with reduction of possible leakage and healing of the tracheal tear could be achieved. CONCLUSION: Management of tracheal tears is complex; in severe cases special therapy concepts such as the use of V-V ECMO may become necessary.

YouTube-videos for patient education in lymphangioleiomyomatosis?

BACKGROUND: The Internet is commonly used by patients to acquire health information. To date, no studies have evaluated the quality of information available on YouTube regarding lymphangioleiomyomatosis (LAM). Our aim was to determine the quality and content of YouTube videos regarding LAM and to compare the information provided with current knowledge and guidelines about the disease. METHODS: The first 200 video hits on YouTube in English for the search term "lymphangioleiomyomatosis" were recorded. All videos suitable for patient education on LAM were included. Video quality was analyzed independently by two investigators utilizing the Health on the Net (HONcode) score, which assesses whether websites provide understandable, accessible, and trustworthy health information; the DISCERN score, which evaluates the quality of information about treatment decisions; and a newly developed LAM-related content score (LRCS) with 31 guideline elements. RESULTS: The search identified 64 eligible videos. The "engagement rate" of 0.3 was low, with a median number of views of 408 (range 42-73,943), a median of 4 likes (range 0-2082), and the majority (53%) receiving a low HONcode score (≤ 2) and only 10% of videos achieving a high score (> 5). The median DISCERN score was 28 (range 15-61, maximum possible score 80), indicating poor video quality and reliability. The median LRCS was 8 (range 0-29, maximum possible score 31) and videos frequently failed to provide sources of information. CONCLUSIONS: Online resources could contribute to the limited and often inaccurate information available to patients with LAM, with only a few YouTube videos providing high-quality patient-relevant information.

Profibrotic epithelial TGF-ß1 signaling involves NOX4-mitochondria cross talk and redox-mediated activation of the tyrosine kinase FYN.

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed redox balance and increased production of reactive oxygen species (ROS), which is believed to contribute to epithelial injury and fibrotic lung scarring. The main pulmonary sources of ROS include mitochondria and NADPH oxidases (NOXs), of which the NOX4 isoform has been implicated in IPF. Non-receptor SRC tyrosine kinases (SFK) are important for cellular homeostasis and are often dysregulated in lung diseases. SFK activation by the profibrotic transforming growth factor-ß (TGF-ß) is thought to contribute to pulmonary fibrosis, but the relevant SFK isoform and its relationship to NOX4 and/or mitochondrial ROS in the context of profibrotic TGF-ß signaling is not known. Here, we demonstrate that TGF-ß1 can rapidly activate the SRC kinase FYN in human bronchial epithelial cells, which subsequently induces mitochondrial ROS (mtROS) production, genetic damage shown by the DNA damage marker γH2AX, and increased expression of profibrotic genes. Moreover, TGF-ß1-induced activation of FYN involves initial activation of NOX4 and direct cysteine oxidation of FYN, and both FYN and mtROS contribute to TGF-ß-induced induction of NOX4. NOX4 expression in lung tissues of IPF patients is positively correlated with disease severity, although FYN expression is down-regulated in IPF and does not correlate with disease severity. Collectively, our findings highlight a critical role for FYN in TGF-ß1-induced mtROS production, DNA damage response, and induction of profibrotic genes in bronchial epithelial cells, and suggest that altered expression and activation of NOX4 and FYN may contribute to the pathogenesis of pulmonary fibrosis.

Cost drivers in the pharmacological treatment of interstitial lung disease.

INTRODUCTION: Treatments of interstitial lung diseases (ILDs) mainly focus on disease stabilization and relief of symptoms by managing inflammation or suppressing fibrosis by (in part costly) drugs. To highlight economic burden of drug treatment in different ILD-subtypes we assessed cost trends and therewith-associated drivers. METHODS: Using data from the German, observational HILDA study we estimated adjusted mean medication costs over 36-month intervals using one- and two-part Generalized Estimating Equation (GEE) regression models with a gamma distribution and log link. Next, we determined factors associated with costs. RESULTS: In Idiopathic pulmonary fibrosis (IPF) mean per capita medication costs increased from €1442 before to €11,000€ at the end of study. In non-IPF subtypes, the increase took place at much lower level. Mean per capita ILD-specific medication costs at the end of the study ranged between €487 (other ILD) and €9142 (IPF). At baseline, higher FVC %predicted values were associated with lower medication costs in IPF (-9%) and sarcoidosis (-1%). During follow up higher comorbidity burden escalated costs in progressive fibrosing ILD (PF-ILD) (+52%), sarcoidosis (+60%) and other ILDs (+24%). The effect of disease duration was not uniform, with cost savings in PF-ILD (-8%) and sarcoidosis (-6%), but increased spending in IPF (+11%). CONCLUSION: Pharmacological management of ILD, in particular of IPF imposes a substantial economic burden on the healthcare system. Strategies to reduce comorbidity burden and early treatment may reduce the impact of ILDs on the healthcare system.

[Exacerbation in Idiopathic Pulmonary Fibrosis]. / Akute Exazerbation der idiopathischen Lungenfibrose.

Acute exacerbations (AE) are a life-threatening complication in patients with idiopathic pulmonary fibrosis (IPF). In-hospital mortality is high and the overall prognosis poor. The underlying causes of AE-IPF still remain unclear and there are no focused guidelines for its management. In most cases high-dose steroids combined with an antibiotic therapy are applied. Preventive and palliative measures are very important. Intensive research is necessary to improve management of AE-IPF.

Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry.

OBJECTIVE: There is a paucity of observational data on antifibrotic therapy for idiopathic pulmonary fibrosis (IPF). We aimed to assess the course of disease of IPF patients with and without antifibrotic therapy under real-life conditions. METHODS: We analysed data from a non-interventional, prospective cohort study of consecutively enrolled IPF patients from 20 interstitial lung disease expert centres in Germany. Data quality was ensured by automated plausibility checks, on-site monitoring, and source data verification. Propensity scores were applied to account for known differences in baseline characteristics between patients with and without antifibrotic therapy. RESULTS: Among the 588 patients suitable for analysis, the mean±sd age was 69.8±9.1 years, and 81.0% were male. The mean±sd duration of disease since diagnosis was 1.8±3.4 years. The mean±sd value at baseline for forced vital capacity (FVC) and diffusion capacity (D LCO) were 68.6±18.8% predicted and 37.8±18.5% predicted, respectively. During a mean±sd follow-up of 1.2±0.7 years, 194 (33.0%) patients died. The 1-year and 2-year survival rates were 87% versus 46% and 62% versus 21%, respectively, for patients with versus without antifibrotic therapy. The risk of death was 37% lower in patients with antifibrotic therapy (hazard ratio 0.63, 95% CI 0.45; 0.87; p=0.005). The results were robust (and remained statistically significant) on multivariable analysis. Overall decline of FVC and D LCO was slow and did not differ significantly between patients with or without antifibrotic therapy. CONCLUSIONS: Survival was significantly higher in IPF patients with antifibrotic therapy, but the course of lung function parameters was similar in patients with and without antifibrotic therapy. This suggests that in clinical practice, premature mortality of IPF patients eventually occurs despite stable measurements for FVC and D LCO.

Ongoing challenges in pulmonary fibrosis and insights from the nintedanib clinical programme.

The approvals of nintedanib and pirfenidone changed the treatment paradigm in idiopathic pulmonary fibrosis (IPF), and increased our understanding of the underlying disease mechanisms. Nonetheless, many challenges and unmet needs remain in the management of patients with IPF and other progressive fibrosing interstitial lung diseases.This review describes how the nintedanib clinical programme has helped to address some of these challenges. Data from this programme have informed changes to the IPF diagnostic guidelines, the timing of treatment initiation, and the assessment of disease progression. The use of nintedanib to treat patients with advanced lung function impairment, concomitant emphysema, patients awaiting lung transplantation and patients with IPF and lung cancer is discussed. The long-term use of nintedanib and an up-to-date summary of nintedanib in clinical practice are discussed. Directions for future research, namely emerging therapeutic options, precision medicine and other progressive fibrosing interstitial lung diseases, are described.Further developments in these areas should continue to improve patient outcomes.

Determinants of health-related quality of life decline in interstitial lung disease.

BACKGROUND: Health-related quality of life (HRQL) in interstitial lung disease (ILD) patients is impaired. We aimed to identify baseline predictors for HRQL decline within a 12-month observation period. METHODS: We analyzed 194 ILD patients from two German ILD-centers in the observational HILDA study. We employed the disease-specific King's Brief Interstitial Lung Disease questionnaire (K-BILD) with the subdomains 'psychological impact', 'chest symptoms' and 'breathlessness and activities', and the generic EQ-5D Visual Analog Scale (VAS). We evaluated how many patients experienced a clinically meaningful decline in HRQL. Subsequently, we investigated medical and sociodemographic factors as potential predictors of HRQL deterioration. RESULTS: Within the study population (34.0% male, Ø age 61.7) mean HRQL scores hardly changed between baseline and follow up (K-BILD: 52.8 vs. 52.5 | VAS: 60.0 vs. 57.3). On the intra-individual level, 30.4% (n = 59) experienced a clinically relevant deterioration in K-BILD total score and 35.4% (n = 68) in VAS. Lower baseline forced vital capacity (FVC) % predicted determined HRQL decline in K-BILD total score (ß-coefficient: - 0.02, p = 0.007), VAS (ß-coefficient: - 0.03, p < 0.0001), and in the subdomain 'psychological impact' (ß-coefficient: - 0.02, p = 0.014). Lower baseline diffusing capacity of carbon monoxide (DLCO) % predicted determined deterioration in 'breathlessness and activities' (ß-coefficient: - 0.04, p = 0.003) and 'chest symptoms' (ß-coefficient: - 0.04, p = 0.002). Additionally, increasing age predicted decline in 'psychological impact' (ß-coefficient: 0.06, p < 0.007). CONCLUSION: Around a third of ILD patients experienced a clinically relevant HRQL deterioration in a 12-month period, which was associated with baseline lung function values in all K-BILD domains. As lung function values are time-dependent variables with possible improvements, in contrast to age and ILD subtype, it, thus, seems important to improve lung function and prevent its decline in order to maintain HRQL on the possibly highest level.

A Comparison of Existing Questionnaires for Identifying the Causes of Interstitial and Rare Lung Diseases.

BACKGROUND: A thorough diagnostic process is essential with regard to prognosis and treatment of the more than 200 different types of interstitial lung diseases (ILD). Key to this complex process is a comprehensive medical history. For this, a template is recommended and questionnaires are increasingly used. Yet, the optimal questionnaire has not been established. OBJECTIVES: We aimed to compare well-established questionnaires that are used in the diagnostic process of interstitial and rare lung diseases. METHODS: Via a structured internet search and ILD expert interviews, we identified 6 different questionnaires for the diagnosis of ILDs: the questionnaires developed by the German Respiratory Society (DGP), American College of Chest Physicians (ACCP), National Jewish Health (NJH), Österreichische Röntgengesellschaft/Gesellschaft für Medizinische Radiologie und Nuklearmedizin (OERG), University of California, Los Angeles Health (UCLA), and University of California, San Francisco Medical Center (UCSF). We compared the forms, lengths, and contents of the 6 questionnaires regarding symptoms, comorbidities, drug history, previous ILD therapies, family history, smoking habits, occupational history, exposures, travel history, and former diagnostic procedures. RESULTS: The questionnaires differed in length and content. The UCLA questionnaire focuses on connective tissue diseases extensively, while the NJH questionnaire captures previous diagnostics in detail. The OERG questionnaire is condensed, while the other 5 questionnaires are very detailed. The UCSF questionnaire contains a personal assessment part for the patient. For the majority of the questions, the patient can choose options from a preselected list of possible answers. The DGP questionnaire offers the patient the opportunity to add additional information in the form of free text to some of the key questions. CONCLUSIONS: Questionnaires are an important tool in the diagnostic process of ILDs. Further validation and adjustment to clinical guidelines will help to improve existing questionnaires. Future work must aim to develop an internationally accepted template.

Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.

BACKGROUND: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients. OBJECTIVES: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin. METHODS: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples. RESULTS: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG. CONCLUSIONS: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).

The clinical course of idiopathic pulmonary fibrosis and its association to quality of life over time: longitudinal data from the INSIGHTS-IPF registry.

BACKGROUND: Quality of life (QoL) is profoundly impaired in patients with idiopathic pulmonary fibrosis (IPF). However, data is limited regarding the course of QoL. We therefore analysed longitudinal data from the German INSIGHTS-IPF registry. METHODS: Clinical status and QoL were assessed at enrollment and subsequently at 6- to 12-months intervals. A range of different QoL questionnaires including the St. George's Respiratory Questionnaire (SGRQ) were used. RESULTS: Data from 424 patients were included; 76.9% male; mean age 68.7 ± 9.1 years, mean FVC% predicted 75.9 ± 19.4, mean DLCO% predicted 36.1 ± 15.9. QoL worsened significantly during follow-up with higher total SGRQ scores (increased by 1.47 per year; 95% CI: 1.17 to 1.76; p < 0.001) and higher UCSD-SOBQ scores and lower EQ-5D VAS and WHO-5 scores. An absolute decline in FVC% predicted of > 10% was associated with a significant deterioration in SGRQ (increasing by 9.08 units; 95% CI: 2.48 to 15.67; p = 0.007), while patients with stable or improved FVC had no significantly change in SGRQ. Patients with a > 10% decrease of DLCO % predicted also had a significant increase in SGRQ (+ 7.79 units; 95% CI: 0.85 to 14.73; p = 0.028), while SQRQ was almost stable in patients with stable or improved DLCO. Patients who died had a significant greater increase in SGRQ total scores (mean 11.8 ± 18.6) at their last follow-up visit prior to death compared to survivors (mean 4.2 ± 18.9; HR = 1.03; 95% CI: 1.01 to 1.04; p < 0.001). All QoL scores across the follow-up period were significantly worse in hospitalised patients compared to non-hospitalised patients, with the worst scores reported in those hospitalised for acute exacerbations. CONCLUSIONS: QoL assessments in the INSIGHTS-IPF registry demonstrate a close relationship between QoL and clinically meaningful changes in lung function, comorbidities, disease duration and clinical course of IPF, including hospitalisation and mortality.

Possible value of antifibrotic drugs in patients with progressive fibrosing non-IPF interstitial lung diseases.

BACKGROUND: Fibrosing, non-idiopathic pulmonary fibrosis (non-IPF) interstitial lung diseases (fILDs) are a heterogeneous group of diseases characterized by a different amount of inflammation and fibrosis. Therapy is currently based on corticosteroids and/or immunomodulators. However, response to these therapies is highly variable, sometimes without meaningful improvement, especially in more fibrosing forms. Pirfenidone and nintedanib have recently demonstrated to reduce functional decline in patients with IPF. However, their antifibrotic mechanism makes these two drugs an interesting approach for treatment of fibrosing ILDs other than IPF. OBJECTIVES: We here report our experience with antifibrotic drugs in fibrosing non-IPF ILDs patients having a progressive phenotype during immunosuppressive therapy. METHODS: Patients with a multidisciplinary team diagnosis of fibrosing non-IPF ILDs experiencing a progressive phenotype during treatment with corticosteroids and/or immunomodulators between October-2014 and January-2018 at our tertiary referral Center for ILDs were retrospectively analyzed. Antifibrotic therapy was administered after application with the respective health insurance company and after consent by the patient. Pulmonary-function-tests and follow-up visits were performed every 6 ± 1 months. RESULTS: Eleven patients were treated with antifibrotic drugs (8 males, mean age 62 ± 12.8 years, mean FVC% 62.8 ± 22.3, mean DLCO% 35.5 ± 10.7, median follow-up under antifibrotic treatment 11.1 months). Patients had a diagnosis of unclassifiable ILD in 6 cases, pleuroparenchymal fibroelastosis in 2 cases, idiopathic-NSIP in 1 case, asbestos-related ILD in 1 case and Hermansky-Pudlak syndrome in 1 case. Treatment before antifibrotics consisted of corticosteroids in all patients: 5 combined with Azathioprin, 1 with either methotrexate or cyclophosphamide (i.v.). Ten patients were treated with pirfenidone (2403 mg/die) and 1 with nintedanib (300 mg/die). Median FVC was 56, 56, 50%, at time points - 24, - 12, - 6 before initiation, 44% at time of initiation and 46.5% at 6 months after initiation of antifibrotic treatment. Antifibrotic treatment was generally well tolerated with a need of dose reduction in 2 cases (rash and nausea) and early termination in 3 cases. CONCLUSIONS: Antifibrotic treatment may be a valuable treatment option in patients with progressive fibrosing non-IPF ILD if currently no other treatment options exist. However, prospective, randomized clinical trials are urgently needed to assess the real impact of antifibrotic therapy in these patients.

C-proSP-B: A Possible Biomarker for Pulmonary Diseases?

BACKGROUND: Detection of surfactant proteins A and D (SP-A and SP-D) in the serum of patients with pulmonary diseases is thought to reflect an injury of the alveolar epithelial barrier and as such serve as a biomarker for these diseases. However, the data for SP-B are limited. OBJECTIVES: The aim of this feasibility study was to assess whether immature SP-B pre-proteins might have value as a possible biomarker for pulmonary diseases. METHODS: In serum samples from patients with different chronic lung diseases (interstitial lung diseases [ILDs], chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary hypertension, inflammation, patients on ventilator support; total n = 283), C-proSP-B was measured using an electrochemiluminescence immunoassay based on mouse monoclonal anti-C-proSP-B antibodies. Levels were correlated to lung functional and clinical parameters. RESULTS: The highest C-proSP-B levels were detected in the serum of idiopathic pulmonary fibrosis (IPF) patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). No significant correlations were found between C-proSP-B levels and lung function, smoking history, or disease extent. CONCLUSIONS: SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage such as ILDs, especially in IPF. Their role in the long-term monitoring of such diseases has to be clarified further.

Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease.

RATIONALE: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease. OBJECTIVES: To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease. METHODS: We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis. MEASUREMENTS AND MAIN RESULTS: Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease. CONCLUSIONS: Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.

Blood-sampling collection prior to surgery may have a significant influence upon biomarker concentrations measured.

BACKGROUND: Biomarkers can be subtle tools to aid the diagnosis, prognosis and monitoring of therapy and disease progression. The validation of biomarkers is a cumbersome process involving many steps. Serum samples from lung cancer patients were collected in the framework of a larger study for evaluation of biomarkers for early detection of lung cancer. The analysis of biomarker levels measured revealed a noticeable difference in certain biomarker values that exhibited a dependence of the time point and setting of the sampling. Biomarker concentrations differed significantly if taken before or after the induction of anesthesia and if sampled via venipuncture or arterial catheter. METHODS: To investigate this observation, blood samples from 13 patients were drawn 1-2 days prior to surgery (T1), on the same day by venipuncture (T2) and after induction of anesthesia via arterial catheter (T3). The biomarkers Squamous Cell Carcinoma antigen (CanAG SCC EIA, Fujirebio Diagnostics, Malvern, USA), Carcinoembrionic Antigen (CEA), and CYFRA 21-1 (Roche Diagnostics GmbH, Mannheim, Germany) were analyzed. RESULTS: SCC showed a very strong effect in relation to the sampling time and procedure. While the first two points in time (T1; T2) were highly comparable (median fold-change: 0.84; p = 0.7354; correlation ρ = 0.883), patients showed a significant increase (median fold-change: 4.96; p = 0.0017; correlation ρ = -0.036) in concentration when comparing T1 with the sample time subsequent to anesthesia induction (T3). A much weaker increase was found for CYFRA 21-1 at T3 (median fold-change: 1.40; p = 0.0479). The concentration of CEA showed a very small, but systematic decrease (median fold-change: 0.72; p = 0.0039). CONCLUSIONS: In this study we show the unexpectedly marked influence of blood withdrawal timing (before vs. after anesthesia) and procedure (venous versus arterial vessel puncture) has on the concentration of the protein biomarker SCC and to a less extent upon CYFRA21-1. The potential causes for these effects remain to be elucidated in subsequent studies, however these findings highlight the importance of a standardized, controlled blood collection protocol for biomarker detection.