Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease.

Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

[Latest news on RA-ILD]. / Aktuelles zur RA-ILD.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is of high clinical relevance. It not only affects the quality of life but also makes a significant contribution to the mortality rate of patients with rheumatoid arthritis. RA-ILD can present with all known radiological and histopathological patterns seen in other interstitial pneumonias. Among these pneumonias, diffuse alveolar damage (DAD), followed by usual interstitial pneumonia (UIP) has the worst prognosis. In addition, acute exacerbation of RA-ILD, which can occur at any time during the disease, is highly lethal. An algorithm for the diagnosis and treatment of RA-ILD is pending and will be addressed in the following article. In addition to immunosuppressants and disease-modifying antirheumatic drugs (DMARD), antifibrotics have recently gained importance in the therapy of RA-ILD.

Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-ß1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

[Hypersensitivity Pneumonitis - an important differential diagnosis of infiltrative lung diseases]. / Exogen allergische Alveolitis ­ Eine wichtige Differenzialdiagnose der infiltrativen Lungenerkrankungen.

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic disease of the lung parenchyma and terminal bronchioles caused by an allergic reaction to inhaled antigens. The immune response following antigen exposure results in lymphocytic inflammation as well as granuloma formation.The typical histologic pattern of HP consists of cellular interstitial pneumonia, cellular bronchiolitis, and epithelioid cell granulomas. The additional presence of fibrosis has a significant impact on the course as well as the prognosis of the disease and represents a therapeutic approach. Therefore, a classification into a non-fibrotic and a fibrotic phenotype is proposed.The diagnosis of HP is made by high-resolution computed tomography (HRCT) of the lung, evaluation of possible antigen exposure, and bronchoscopy with bronchoalveolar lavage and, if necessary, forceps biopsy. If the diagnosis is inconclusive, transbronchial cryobiopsy or surgical lung biopsy may need to follow. A multidisciplinary board is critical in making the diagnosis.

IL23R on myeloid cells is involved in murine pulmonary granuloma formation.

PURPOSE OF THE STUDY: The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.

Sarcoidosis involvement of the diaphragm leading to right diaphragmatic elevation: a case report.

A 69-year-old male Caucasian presenting with dyspnea on exertion related to unilateral diaphragmatic dysfunction as caused by sarcoidosis is described. First, right diaphragmatic elevation was unexplained, while the patient presented with a restrictive pattern in lung function testing using bodyplethysmography and with reduced global and diaphragmatic respiratory muscle strength as evidenced by respiratory pressures. Subsequently, surgical diaphragm plication was performed, unfortunately, without any clinical improvement. Microscopic examination of diaphragm sections revealed a lymphocytic myositis with granulomatous pleuritis showing multiple non-caseating epithelioid granulomas. Accordingly, a lymphocytic alveolitis (26% lymphocytes) with an elevated CD4/CD8 T cell ratio of 8.0% and elevated serum parameters (neopterin and sIL-2 receptor) were established. Consequently, the diagnosis of pulmonary sarcoidosis with diaphragm involvement but without extrapulmonary involvement has been established. Therefore, sarcoidosis needs to be considered in any patient presenting with unilateral diaphragmatic dysfunction. The optimal treatment strategy, however, needs to be established in the future.

Endoscopic Lung Volume Reduction in COPD: The Impact of Coil Implantation on Patients' Physical Activity.

Endoscopic lung volume reduction (ELVR) is an emerging therapy option for the treatment of severe emphysema in COPD. To which extent patients profit from lung volume reduction via coils (LVRC) regarding morbidity, mortality, and quality of life is not clear yet. In this monocentric prospective cohort study, 13 COPD patients with severe emphysema (residual volume [RV] >225%) were enrolled at the University Hospital of Bonn. Activity measurements were assessed by a validated accelerometer wristband. By LVRC, RV could be reduced by 0.13 L to 5.54 ± 1.29 L. We could show a clinically relevant improvement in patients' physical activity after LVRC, measured as daily step count (497.7 ± 72.6 vs. 1,913.7 ± 182.7 steps/day, p = 0.03) and mean daily active energy expenditure (714.4 ± 73.6 vs. 2,321.3 ± 163.9 joules, p = 0.03). This improvement in physical activity is possibly associated with a positive effect on patients' morbidity and mortality.

Regional expiratory time constants in severe respiratory failure estimated by electrical impedance tomography: a feasibility study.

BACKGROUND: Electrical impedance tomography (EIT) has been used to guide mechanical ventilation in ICU patients with lung collapse. Its use in patients with obstructive pulmonary diseases has been rare since obstructions could not be monitored on a regional level at the bedside. The current study therefore determines breath-by-breath regional expiratory time constants in intubated patients with chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). METHODS: Expiratory time constants calculated from the global impedance EIT signal were compared to the pneumatic volume signals measured with an electronic pneumotachograph. EIT-derived expiratory time constants were additionally determined on a regional and pixelwise level. However, regional EIT signals on a single pixel level could in principle not be compared with similar pneumatic changes since these measurements cannot be obtained in patients. For this study, EIT measurements were conducted in 14 intubated patients (mean Simplified Acute Physiology Score II (SAPS II) 35 ± 10, mean time on invasive mechanical ventilation 36 ± 26 days) under four different positive end-expiratory pressure (PEEP) levels ranging from 10 to 17 cmH2O. Only patients with moderate-severe ARDS or COPD exacerbation were included into the study, preferentally within the first days following intubation. RESULTS: Spearman's correlation coefficient for comparison between EIT-derived time constants and those from flow/volume curves was between 0.78 for tau (τ) calculated from the global impedance signal up to 0.83 for the mean of all pixelwise calculated regional impedance changes over the entire PEEP range. Furthermore, Bland-Altman analysis revealed a corresponding bias of 0.02 and 0.14 s within the limits of agreement ranging from - 0.50 to 0.65 s for the aforementioned calculation methods. In addition, exemplarily in patients with moderate-severe ARDS or COPD exacerbation, different PEEP levels were shown to have an influence on the distribution pattern of regional time constants. CONCLUSIONS: EIT-based determination of breath-by-breath regional expiratory time constants is technically feasible, reliable and valid in invasively ventilated patients with severe respiratory failure and provides a promising tool to individually adjust mechanical ventilation in response to the patterns of regional airflow obstruction. TRIAL REGISTRATION: German Trial Register DRKS 00011650 , registered 01/31/17.

Respiratory muscle involvement in sarcoidosis.

INTRODUCTION: In sarcoidosis, muscle involvement is common, but mostly asymptomatic. Currently, little is known about respiratory muscle and diaphragm involvement and function in patients with sarcoidosis. Reduced inspiratory muscle strength and/or a reduced diaphragm function may contribute to exertional dyspnea, fatigue and reduced health-related quality of life. Previous studies using volitional and non-volitional tests demonstrated a reduced inspiratory muscle strength in sarcoidosis compared to control subjects, and also showed that respiratory muscle function may even be significantly impaired in a subset of patients. Areas covered: This review examines the evidence on respiratory muscle involvement and its implications in sarcoidosis with emphasis on pathogenesis, diagnosis and treatment of respiratory muscle dysfunction. The presented evidence was identified by a literature search performed in PubMed and Medline for articles about respiratory and skeletal muscle function in sarcoidosis through to January 2018. Expert commentary: Respiratory muscle involvement in sarcoidosis is an underdiagnosed condition, which may have an important impact on dyspnea and health-related quality of life. Further studies are needed to understand the etiology, pathogenesis and extent of respiratory muscle involvement in sarcoidosis.