[Statement paper on the implementation of a national organized program in Germany for the early detection of lung cancer in risk populations using low-dose CT screening including management of screening findings]. / Positionspapier zur Implementierung eines nationalen organisierten Programms in Deutschland zur Früherkennung von Lungenkrebs in Risikopopulationen mittels Low-dose-CT-Screening inklusive Management von abklärungsbedürftigen Screeningbefunden.

The process of implementing early detection of lung cancer with low-dose CT (LDCT) in Germany has gained significant momentum in recent years. It is expected that the ordinance of the Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) on the early detection of lung cancer, which has been commented on by the professional societies, will come into effect by the end of 2023. Based on this regulation, the Federal Joint Committee (G-BA) will set up a program for early lung cancer detection with LDCT in the near future. In this position paper, the specialist societies involved in lung cancer screening present key points for a uniform, structured and quality-assured early detection program for lung cancer in Germany to make a constructive contribution to this process. CITATION FORMAT: · Vogel-Claussen J, Blum TG, Andreas S et al. Position paper on the implementation of a nationally organized program in Germany for the early detection of lung cancer in high-risk populations using low-dose CT screening including the management of screening findings requiring further workup. Fortschr Röntgenstr 2024; 196: DOI 10.1055/a-2178-2846.

[Statement paper on the implementation of a national organized program in Germany for the early detection of lung cancer in risk populations using low-dose CT screening including management of screening findings]. / Positionspapier zur Implementierung eines nationalen organisierten Programms in Deutschland zur Früherkennung von Lungenkrebs in Risikopopulationen mittels Low-dose-CT-Screening inklusive Management von abklärungsbedürftigen Screeningbefunden.

The process of implementing early detection of lung cancer with low-dose CT (LDCT) in Germany has gained significant momentum in recent years. It is expected that the ordinance of the Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) on early detection of lung cancer, which has been commented on by the professional societies, will come into effect by the end of 2023. Based on this regulation, the Federal Joint Committee (G-BA) will set up a program for early lung cancer detection with LDCT in the near future. In this position paper, the specialist societies involved in lung cancer screening present concrete cornerstones for a uniform, structured and quality-assured early detection program for lung cancer in Germany to make a constructive contribution to this process.

[Statement Paper on the Implementation of a National Organized Program in Germany for the Early Detection of Lung Cancer in Risk Populations Using Low-dose CT Screening Including Management of Screening Findings]. / Positionspapier zur Implementierung eines nationalen organisierten Programms in Deutschland zur Früherkennung von Lungenkrebs in Risikopopulationen mittels Low-Dose-CT-Screening inklusive Management von abklärungsbedürftigen Screening-Befunden.

The process of implementing early detection of lung cancer with low-dose CT (LDCT) in Germany has gained significant momentum in recent years. It is expected that the ordinance of the Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) on early detection of lung cancer, which has been commented on by the professional societies, will come into effect by the end of 2023. Based on this regulation, the Federal Joint Committee (G-BA) will set up a program for early lung cancer detection with LDCT in the near future. In this position paper, the specialist societies involved in lung cancer screening present concrete cornerstones for a uniform, structured and quality-assured early detection program for lung cancer in Germany to make a constructive contribution to this process.

Diffuse Alveolar Hemorrhage Associated with Epithelioid Angiosarcoma of the Lung: A Challenging Diagnosis.

A 68-year-old patient presented with persistent hemoptysis and weight loss. A CT scan showing diffuse bilateral ground-glass opacities and nodules was followed by bronchoscopy. While diffuse alveolar hemorrhage (DAH) could be seen, specimens obtained during bronchoscopy did not provide conclusive histological findings. The decision was made to conduct video-assisted wedge resection, after which histological examinations revealed the diagnosis of bifocal nodular manifestation of an epithelioid angiosarcoma in the lung. Being a rare entity even among sarcomas, these kinds of tumors can be primary lung tissue angiosarcomas or metastatic lesions with primaries in places like the skin, breast, and heart. Treatment usually includes chemotherapy, but prognosis remains grim. This case highlights that in DAH, uncommon causes should be considered, and sufficient probe gathering is the key to early diagnosis and treatment.

Transcriptomic comparison of primary human lung cells with lung tissue samples and the human A549 lung cell line highlights cell type specific responses during infections with influenza A virus.

Influenza A virus (IAV) causes pandemics and annual epidemics of severe respiratory infections. A better understanding of the molecular regulation in tissue and cells upon IAV infection is needed to thoroughly understand pathogenesis. We analyzed IAV replication and gene expression induced by IAV strain H3N2 Panama in isolated primary human alveolar epithelial type II cells (AECIIs), the permanent A549 adenocarcinoma cell line, alveolar macrophages (AMs) and explanted human lung tissue by bulk RNA sequencing. Primary AECII exhibit in comparison to AM a broad set of strongly induced genes related to RIG-I and interferon (IFN) signaling. The response of AECII was partly mirrored in A549 cells. In human lung tissue, we observed induction of genes unlike in isolated cells. Viral RNA was used to correlate host cell gene expression changes with viral burden. While relative induction of key genes was similar, gene abundance was highest in AECII cells and AM, while weaker in the human lung (due to less IAV replication) and A549 cells (pointing to their limited suitability as a model). Correlation of host gene induction with viral burden allows a better understanding of the cell-type specific induction of pathways and a possible role of cellular crosstalk requiring intact tissue.

Value of 18F FDG-PET/CT parameters on long term follow-up for patients with non-small cell lung cancer.

Objectives: The purpose of this study was to investigate the value of PET/CT in the preoperative staging of non-small cell lung cancer in predicting long-term survival and diagnostic performance, validated by histopathology following surgical resection. Methods: Between 02/2009 and 08/2011, 255 patients with non-small cell lung cancer were included in this single-center prospective study. All underwent 18F FDG-PET/CT for pre-operative staging, and in 243 patients complete surgical resection was possible. Regarding lymph node involvement and extrathoracic metastases, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using the histopathological staging as reference. Median follow-up for censored patients was 9.1 years. Results: Overall 5-year survival rate of all patients was 55.6%, and of patients who had complete surgical resection it was 58.2%. In multivariate analysis of all surgically resected patients lymph node involvement (p=0.029) and age >61 years (p=<0.001) were significant independent prognostic factors. SUVmax and SUVmean cut-offs between SUV 2 and 11, however, were not associated with better or ;worse survival. The PET-CT sensitivity, specificity, positive predictive value and negative predictive value for predicting lymph node involvement were 57, 95, 88, and 76%, respectively. Furthermore, sensitivity, specificity, positive predictive value, and negative predictive value for detecting extrathoracic metastases were 100, 58, 98, and 100%, respectively. Conclusions: In this study, tumor 18F FDG-uptake values did not provide additional prognostic information. Age>61 years and lymph node metastasis were associated with worse long-term survival in surgically resected patients. 18F FDG-PET/CT scans allow for improved patient selection. However, in staging mediastinal lymph nodes, there is a high rate of false positives and false negatives, suggesting that tissue biopsy is still indicated in many cases.

Human alveolar progenitors generate dual lineage bronchioalveolar organoids.

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280+/EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3ß inhibitor, CHIR99021. By RNA-seq profiling of GSK-3ß knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction.

Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.

Is Adjuvant Radiochemotherapy Always Mandatory in Patients with Resected N2 Non-Small Cell Lung Cancer?

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), the pathologic union for international cancer control (UICC) stage IIIA is a heterogeneous entity, with different forms of N2-lymph node involvement representing different prognoses. Although a multimodality treatment approach, including surgery, systemic therapy, and/or radiotherapy, is almost always recommended, in this retrospective observational study, we sought to determine whether long-term survival might be possible in selected patients who are treated with complete surgical resection alone. METHODS: Between 2013 and 2018, we retrospectively identified 24 patients with NSCLC (16 men and 8 women), who were found to have pathologic N2-lymph node involvement, and were treated with complete surgical lung resection and systematic mediastinal and hilar lymph node dissection but no neoadjuvant or adjuvant treatment. RESULTS: The most frequent reason (n = 14) for forgoing adjuvant treatment was patient refusal. The mean overall survival (OS) was 34.5 months (interquartile range [IQR]: 15.5-53.5 months). The mean disease-free survival (DFS) was 18 months (IQR: 4.75-46.75 months). We identified five patients who survived at least 5 years without recurrence (21%). In each of these cases, the nodal metastases were restricted to a single level and no extracapsular lymph node involvement were detected. Additionally, worse DFS was associated with pT3/4 (vs. a lower T-stage), as well as microscopic lymphovascular invasion. CONCLUSION: Although the small sample size precludes any definitive conclusions, it was possible to demonstrate that long-term survival without neoadjuvant and adjuvant treatment is possible in some patients if complete tumor and nodal resection is performed.

Circulating long non-coding RNA GAS5 (growth arrest-specific transcript 5) as a complement marker for the detection of malignant mesothelioma using liquid biopsies.

BACKGROUND: For the detection of malignant mesothelioma additional markers are needed besides the established panel consisting of calretinin and mesothelin. The aim of this study was the identification and verification of long non-coding RNAs (lncRNAs) as complementing circulating markers. METHODS: Candidate lncRNAs were identified in silico using previously published RNA expression profiles and verified using quantitative PCR (qPCR) in mesothelioma cell lines as well as human plasma samples from mesothelioma patients and asbestos-exposed controls. RESULTS: GAS5 (growth arrest-specific transcript 5) as a single marker is marked by a low sensitivity of 14%, but the combination of GAS5 with calretinin and mesothelin increased the panel's sensitivity from 64 to 73% at a predefined specificity of 97%. Circulating GAS5 is not affected by pleurectomy before blood collection, age, or smoking status. CONCLUSIONS: GAS5 is verified as an appropriate circulating marker for the supplement of calretinin and mesothelin to detect malignant mesothelioma. Although the sensitivity of GAS5 is too low for the use as a single marker, the addition of GAS5 as a third marker improves the performance of the established marker panel. The benefit of GAS5 for the detection of malignant mesothelioma at early stages needs to be validated in a prospective study.

Autoimmune disorders and paraneoplastic syndromes in thymoma.

Thymomas are counted among the rare tumour entities which are associated with autoimmune disorders (AIDs) and paraneoplastic syndromes (PNS) far more often than other malignancies. Through its complex immunological function in the context of the selection and maturation of T cells, the thymus is at the same time highly susceptible to disruptive factors caused by the development and growth of thymic tumours. These T cells, which are thought to develop to competent immune cells in the thymus, can instead adopt autoreactive behaviour due to the uncontrolled interplay of thymomas and become the trigger for AID or PNS affecting numerous organs and tissues within the human body. While myasthenia gravis is the most prevalent PNS in thymoma, numerous others have been described, be they related to neurological, cardiovascular, gastrointestinal, haematological, dermatological, endocrine or systemic disorders. This review article sheds light on the pathophysiology, epidemiology, specific clinical features and therapeutic options of the various forms as well as courses and outcomes of AID/PNS in association with thymomas. Whenever suitable and backed by the limited available evidence, the perspectives from both the thymoma and the affected organ/tissue will be highlighted. Specific issues addressed are the prognostic significance of thymectomy on myasthenia gravis and other thymoma-associated AID/PND and further the impact and safety of immunotherapies on AID and PND relating to thymomas.

[Adequate Perioperative Use of Antibiotics in Thoracic Surgery]. / Rationale perioperative Antibiotikatherapie in der Thoraxchirurgie.

INTRODUCTION: Infectious complications after lung resections pose a high burden of perioperative morbidity and mortality. Among other factors, perioperative antibiotic prophylaxis and management of a postoperative pneumonia have an impact on patient outcome. We developed a local clinical pathway for adequate perioperative use of antibiotics. METHODS: We analysed respiratory samples of 200 patients taken before and after lung resection performed in our lung clinic from October 2013 till October 2014. The clinical pathway was based on our local pathogen and resistance pattern as well as on current guidelines and on the principals of antibiotic stewardship. RESULTS: Gram negative bacteria were the predominant pathogens that grew from the samples in the preoperative phase (62%), as well as in the postoperative phase (78%). A significant number of these bacteria showed intrinsic resistance against the commonly used antibiotics for perioperative prophylaxis. This was the case for both the preoperative phase (21%) and the postoperative phase (39%). These findings were integrated into the local clinical pathway. CONCLUSION: The commonly used antibiotics for perioperative prophylaxis in thoracic surgery cover only some of the pathogens responsible for preoperative airway colonisation and postoperative pneumonia. Therefore, perioperative antibiotic prophylaxis should be given as a single shot just before surgery and postoperative pneumonia should be treated as a hospital acquired pneumonia with respect to the local pathogen and resistance pattern.

Prognostic significance of the pattern of pathological N1 lymph node metastases for non-small cell lung cancer.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC) the pathologic lymph node status N1 is a heterogeneous entity, and different forms of lymph node involvement may represent different prognoses. For methodological reasons, the 8th edition of the TNM staging system for NSCLC makes no official changes to the N descriptor. However, there is evidence that different subforms of N1 disease are associated with different prognoses, and it is now recommended that clinicians record the number of affected lymph nodes and nodal stations for further analyses. In this investigation we sought to determine whether patients with different levels and types of N1 lymph node involvement had significantly different 5-year survival rates. METHODS: We retrospectively identified 90 patients with NSCLC (61 men, 29 women), who were treated between 2008 and 2012 and found to have pathologic N1 lymph node involvement and tumor sizes corresponding to T1 or T2. All patients were treated in curative intent with surgical lung resection and systematic mediastinal and hilar lymph node dissection. RESULTS: The overall 5-year survival rate was 56.3%. In the univariate analysis, lower tumor stage and tumor histology other than large-cell carcinoma were significantly associated with better long-term survival. Patients with solitary lymph node metastases also had longer disease-free survival than those with multiple nodal metastases. In the multivariate analysis, large-cell carcinoma and Union for International Cancer Control (UICC) stage IIB were independently associated with worse survival, while pneumonectomy, compared to lobar or sublobar resection, was independently associated with better survival. CONCLUSIONS: Although we did not observe significant prognostic differences between N1 subcategories within our patient population, other analyses may yield different results. Therefore, these data highlight the need for large, well-designed multicenter studies to confirm the clinical significance of N1 subcategories.

Pulmonary nocardiosis in Western Europe-Clinical evaluation of 43 patients and population-based estimates of hospitalization rates.

BACKGROUND: Pulmonary nocardiosis (PN) is an uncommon but potentially life-threatening infection. Most of our knowledge on PN is derived from case reports and small case series. Increasing incidence rates of PN have been reported recently. The aim of this study was to describe the clinical course of and risk factors for PN in four Western European countries and to estimate population-based annual hospitalization rates. METHODS: This was a retrospective evaluation (1995-2011) of the clinical course of and risk factors for PN in patients at 11 hospitals in four European countries (Germany, Austria, Switzerland, and the Netherlands). Population-based estimates of hospitalization rates for PN in Germany (2005 to 2011) were calculated using official German nationwide diagnosis-related groups (DRG) hospital statistics. RESULTS: Forty-three patients fulfilled stringent criteria for proven (n=8) and probable (n=35) PN; seven had extrapulmonary dissemination. For these 43 patients, the major risk factors for PN were immunocompromising (83.7%) and/or pulmonary (58.1%; as only comorbidity in 27.9%) comorbidities. The median duration of PN targeted therapy was 12 weeks. Distinctive patterns of resistance were observed (imipenem susceptibility: Nocardia farcinica 33.3%; Nocardia asteroides 66.7%). The overall mortality rate was 18.9% (50% in disseminated PN). Over time, annual PN hospitalization rates remained unchanged at around 0.04/100000, with the highest rate among men aged 75-84 years (0.24/100000). CONCLUSIONS: PN is a rare, but potentially life-threatening disease, and mainly affects immunocompromised elderly males. Overall, annual hospitalization rates remained stable between 2005 and 2011.

Mycobacterium tuberculosis Invasion of the Human Lung: First Contact.

Early immune responses to Mycobacterium tuberculosis (Mtb) invasion of the human lung play a decisive role in the outcome of infection, leading to either rapid clearance of the pathogen or stable infection. Despite their critical impact on health and disease, these early host-pathogen interactions at the primary site of infection are still poorly understood. In vitro studies cannot fully reflect the complexity of the lung architecture and its impact on host-pathogen interactions, while animal models have their own limitations. In this study, we have investigated the initial responses in human lung tissue explants to Mtb infection, focusing primarily on gene expression patterns in different tissue-resident cell types. As first cell types confronted with pathogens invading the lung, alveolar macrophages, and epithelial cells displayed rapid proinflammatory chemokine and cytokine responses to Mtb infection. Other tissue-resident innate cells like gamma/delta T cells, mucosal associated invariant T cells, and natural killer cells showed partially similar but weaker responses, with a high degree of variability across different donors. Finally, we investigated the responses of tissue-resident innate lymphoid cells to the inflammatory milieu induced by Mtb infection. Our infection model provides a unique approach toward host-pathogen interactions at the natural port of Mtb entry and site of its implantation, i.e., the human lung. Our data provide a first detailed insight into the early responses of different relevant pulmonary cells in the alveolar microenvironment to contact with Mtb. These results can form the basis for the identification of host markers that orchestrate early host defense and provide resistance or susceptibility to stable Mtb infection.

Pneumolysin induced mitochondrial dysfunction leads to release of mitochondrial DNA.

Streptococcus pneumoniae (S.pn.) is the most common bacterial pathogen causing community acquired pneumonia. The pore-forming toxin pneumolysin (PLY) is the major virulence factor of S.pn. and supposed to affect alveolar epithelial cells thereby activating the immune system by liberation of danger-associated molecular patterns (DAMP). To test this hypothesis, we established a novel live-cell imaging based assay to analyse mitochondrial function and associated release of mitochondrial DNA (mtDNA) as DAMP in real-time. We first revealed that bacterially released PLY caused significant changes of the cellular ATP homeostasis and led to morphologic alterations of mitochondria in human alveolar epithelial cells in vitro and, by use of spectral live-tissue imaging, in human alveoli. This was accompanied by strong mitochondrial calcium influx and loss of mitochondrial membrane potential resulting in opening of the mitochondrial permeability transition pore and mtDNA release without activation of intrinsic apoptosis. Moreover, our data indicate cellular mtDNA liberation via microvesicles, which may contribute to S.pn. related pro-inflammatory immune activation in the human alveolar compartment.

Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2.

OBJECTIVES: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. DESIGN: Controlled, in vitro, ex vivo, and in vivo laboratory study. SUBJECTS: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. INTERVENTIONS: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. MEASUREMENTS AND MAIN RESULTS: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1 mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. CONCLUSIONS: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.

A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy.

We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib.

Tyk2 as a target for immune regulation in human viral/bacterial pneumonia.

The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae-induced interleukin (IL)-1ß release. The lack of IL-1ß resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae-induced IL-1ß-GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1ß and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia.