[German S1 Guideline Long-/Post-COVID]. / S1-Leitlinie Long-/Post-COVID.

The German Society of Pneumology initiated 2021 the AWMF S1 guideline Long COVID/Post-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendations describe current Long COVID/Post-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an explicit practical claim and will be developed and adapted by the author team based on the current increase in knowledge.

Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time.

Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91·5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 µl serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34·5%), asthmatic children (78·7%) and adult asthmatics (62·8%) were significantly more often sensitized compared to controls (4·5, 22 and 22·6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1- α and tumor necrosis factor (TNF)- α showed seasonal variability, whereas IL-1ß, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 ß and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects.

[S2k Guideline - Recommendations for Inpatient Therapy of Patients with COVID-19]. / S2k-Leitlinie ­ Empfehlungen zur stationären Therapie von Patienten mit COVID-19.

Since December 2019, the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - Corona Virus-2) has been spreading rapidly in the sense of a global pandemic. This poses significant challenges for clinicians and hospitals and is placing unprecedented strain on the healthcare systems of many countries. The majority of patients with Coronavirus Disease 2019 (COVID-19) present with only mild symptoms such as cough and fever. However, about 6 % require hospitalization. Early clarification of whether inpatient and, if necessary, intensive care treatment is medically appropriate and desired by the patient is of particular importance in the pandemic. Acute hypoxemic respiratory insufficiency with dyspnea and high respiratory rate (> 30/min) usually leads to admission to the intensive care unit. Often, bilateral pulmonary infiltrates/consolidations or even pulmonary emboli are already found on imaging. As the disease progresses, some of these patients develop acute respiratory distress syndrome (ARDS). Mortality reduction of available drug therapy in severe COVID-19 disease has only been demonstrated for dexamethasone in randomized controlled trials. The main goal of supportive therapy is to ensure adequate oxygenation. In this regard, invasive ventilation and repeated prone positioning are important elements in the treatment of severely hypoxemic COVID-19 patients. Strict adherence to basic hygiene, including hand hygiene, and the correct wearing of adequate personal protective equipment are essential when handling patients. Medically necessary actions on patients that could result in aerosol formation should be performed with extreme care and preparation.

[Guideline for the Diagnosis and Treatment of Asthma - Addendum 2020 - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma ­ Addendum 2020.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

Airway pathology in severe asthma is related to airflow obstruction but not symptom control.

BACKGROUND: Patients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment. METHODS: Fifty severe asthmatics received prednisone 40 mg/d for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 µg twice daily + budesonide/formoterol 200/6 µg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction. RESULTS: Airway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta-positive cells within Asm bundles, in addition to lower numbers of chymase-positive mast cells in the submucosa compared to patients with nonpersistent obstruction. CONCLUSIONS: Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.

[Guideline for the Diagnosis and Treatment of COPD Patients - Issued by the German Respiratory Society and the German Atemwegsliga in Cooperation with the Austrian Society of Pneumology]. / Leitlinie zur Diagnostik und Therapie von Patienten mit chronisch obstruktiver Bronchitis und Lungenemphysem (COPD).

This document is a revision of the guideline for diagnosis and treatment of COPD that replaces the version from 2007. A multitude of recent reports regarding risk factors, diagnosis, assessment, prevention and pharmacological as well as non-pharmacological treatment options made a major revision mandatory. The new guideline is based on the GOLD document taking into account specifics in Germany and Austria.

[Guideline for the Diagnosis and Treatment of Asthma - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma.

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma.

Roflumilast for asthma: Efficacy findings in mechanism of action studies.

BACKGROUND: The efficacy profile of roflumilast, a phosphodiesterase-4 inhibitor used for the treatment of chronic obstructive pulmonary disease (COPD), is well known. In asthma treatment, much less is understood about the role of roflumilast, particularly its mechanism of action and potential bronchodilatory effects. AIM: To evaluate the therapeutic efficacy and mechanism of action of roflumilast in patients with asthma using data from eight placebo-controlled, double-blind phase I-III studies. METHODS: The studies were conducted at 14 sites in Europe, North America and South Africa from 1997 to 2005. The effect of treatment with 250 µg, 500 µg or 1000 µg roflumilast was compared with placebo in seven cross-over studies and one parallel-group study in 197 patients 18-70 years of age. Primary endpoints focused on the extent of the late allergic response after an allergen challenge, change in sputum cell eosinophil counts or exhaled nitric oxide (eNO), forced expiratory volume in 1 s (FEV1) and exercise-induced bronchoconstriction. Secondary endpoints included the extent of the early allergic response and measurements of tumour necrosis factor α (TNFα), sputum cells and inflammatory markers. RESULTS: Roflumilast attenuated allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts were also observed and physiologic responses to allergen-induced challenge were confirmed by a significant reduction in TNFα. Side effects were similar to COPD, but did not include weight loss. CONCLUSIONS: The results from these studies indicate that the anti-inflammatory effects of roflumilast observed in COPD are also seen in asthma and advance our understanding of its mechanism of action. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT01365533.

Increased breath naphthalene in children with asthma and wheeze of the All Age Asthma Cohort (ALLIANCE).

Exhaled breath contains numerous volatile organic compounds (VOCs) known to be related to lung disease like asthma. Its collection is non-invasive, simple to perform and therefore an attractive method for the use even in young children. We analysed breath in children of the multicenter All Age Asthma Cohort (ALLIANCE) to evaluate if 'breathomics' have the potential to phenotype patients with asthma and wheeze, and to identify extrinsic risk factors for underlying disease mechanisms. A breath sample was collected from 142 children (asthma: 51, pre-school wheezers: 55, healthy controls: 36) and analysed using gas chromatography-mass spectrometry (GC/MS). Children were diagnosed according to Global Initiative for Asthma guidelines and comprehensively examined each year over up to seven years. Forty children repeated the breath collection after 24 or 48 months. Most breath VOCs differing between groups reflect the exposome of the children. We observed lower levels of lifestyle-related VOCs and higher levels of the environmental pollutants, especially naphthalene, in children with asthma or wheeze. Naphthalene was also higher in symptomatic patients and in wheezers with recent inhaled corticosteroid use. No relationships with lung function or TH2 inflammation were detected. Increased levels of naphthalene in asthmatics and wheezers and the relationship to disease severity could indicate a role of environmental or indoor air pollution for the development or progress of asthma. Breath VOCs might help to elucidate the role of the exposome for the development of asthma. The study was registered at ClinicalTrials.gov (NCT02496468).

Do small airway abnormalities characterize asthma phenotypes? In search of proof.

The role of small airway abnormalities in asthma pathogenesis has been extensively studied and debated for several decades. However, whether or not small airway abnormalities play a relevant role in specific phenotypes of asthmatic patients and contribute to clinical presentation is largely unknown. In the present review, we evaluated available data on the role of small airways in severe asthma, with a further focus on asthma in smokers and asthma in the elderly. These phenotypes are characterized by a poor response to treatment and they can represent a model of greater small airway impairment. In severe asthmatics, small airway involvement has been shown through evidence of both distal inflammation and of increased air trapping. The few available data on asthmatics who smoke, and elderly asthmatics, similarly suggests that small airway abnormalities contribute to the pathogenesis of the disease. In this perspective, there could be a rationale for specifically assessing small airway impairment in these patients and for clinical studies evaluating whether pharmacological approaches targeting the more peripheral airways result in clinical benefits beyond conventional therapy.

[The German centre for lung research - translational research for the prevention, diagnosis and treatment of respiratory diseases]. / Das Deutsche Zentrum für Lungenforschung - Translationale Forschung für Prävention, Diagnose und Therapie von Atemwegserkrankungen.

Respiratory diseases are one of the most important causes of mortality with tremendous costs for health care systems, not only in Germany, but worldwide. Up to now treatment options for most of these chronic diseases are limited. The German Ministry for Research and Education (BMBF) - following the example of the US National Institute of Health have supported the foundation of a German Centre for Lung Research (DZL) to speed up the development of preventive, diagnostic and therapeutic measures. Not only universities, but also non-university based research institutes are part of the DZL. To allow the translation from basic research experience into clinical practice to improve patient care, basic research orientated approaches will be combined with disease and patient focused approaches. The DZL is one of six German Centres for Health Care Research (neurological diseases, diabetes, cardiovascular diseases, infectious diseases, cancer, and lung diseases) for the optimisation of translational processes to overcome the burden of major diseases.

Generation and evaluation of a monoclonal antibody, designated MAdL, as a new specific marker for adenocarcinomas of the lung.

BACKGROUND: Different therapy regimens in non-small-cell lung cancer (NSCLC) are of rising clinical importance, and therefore a clear-cut subdifferentiation is mandatory. The common immunohistochemical markers available today are well applicable for subdifferentiation, but a fraction of indistinct cases still remains, demanding upgrades of the panel by new markers. METHODS: We report here the generation and evaluation of a new monoclonal antibody carrying the MAdL designation, which was raised against primary isolated human alveolar epithelial cells type 2. RESULTS: Upon screening, one clone (MAdL) was identified as a marker for alveolar epithelial cell type II, alveolar macrophages and adenocarcinomas of the lung. In a large-scale study, this antibody, with an optimised staining procedure for formalin-fixed tissues, was then evaluated together with the established markers thyroid transcription factor-1, surfactant protein-A, pro-surfactant protein-B and napsin A in a series of 362 lung cancer specimens. The MAdL displays a high specificity (>99%) for adenocarcinomas of the lung, together with a sensitivity of 76.5%, and is capable of delivering independent additional diagnostic information to the established markers. CONCLUSION: We conclude that MAdL is a new specific marker for adenocarcinomas of the lung, which helps to clarify subdifferentiation in a considerable portion of NSCLCs.

Roflumilast with long-acting ß2-agonists for COPD: influence of exacerbation history.

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting ß(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 µg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

Can anti-IgE therapy prevent airway remodeling in allergic asthma?

Airway remodeling is a central feature of asthma. It is exemplified by thickening of the lamina reticularis and structural changes to the epithelium, submucosa, smooth muscle, and vasculature of the airway wall. Airway remodeling may result from persistent airway inflammation. Immunoglobulin E (IgE) is an important mediator of allergic reactions and has a central role in airway inflammation and asthma-related symptoms. Anti-IgE therapies (such as omalizumab) have the potential to block an early step in the allergic cascade and therefore have the potential to reduce airway remodeling. The reduction in free IgE levels following anti-IgE therapy leads to reductions in high-affinity IgE receptor (FcεRI) expression on mast cells, basophils, and dendritic cells. This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of granulocyte macrophage colony-stimulating factor, interleukin (IL)-2, IL-4, IL-5, and IL-13. Considering the previously demonstrated anti-inflammatory effects of anti-IgE therapy, along with results from a small study showing continued benefit after discontinuation of long-term treatment, a larger study to assess its effect on markers of airway remodeling is underway.

Persistency of response to omalizumab therapy in severe allergic (IgE-mediated) asthma.

BACKGROUND: The physician's global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment of response to omalizumab (XOLAIR®). This randomized, open-label, parallel-group study evaluated the persistency of treatment responder classification in patients receiving omalizumab added to optimized asthma therapy (OAT). METHODS: Patients (12-75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and omalizumab (n = 272) or OAT (n = 128) for 32 weeks. Response or nonresponse was evaluated at Weeks 16 and 32. Response was defined as an investigator's (physician's) GETE rating of excellent or good; nonresponse was defined as a rating of moderate, poor or worsening. RESULTS: Three hundred and forty-nine patients had GETE ratings available at Weeks 16 and 32 (omalizumab n = 258, OAT n = 91). Omalizumab responders of about 171/187 (91.4%)and 44/71 (62.0%) omalizumab nonresponders at Week 16 persisted as responders or nonresponders at Week 32. The investigator's GETE at Week 16 predicted persistency of response or nonresponse to omalizumab at Week 32 for 83.3% (215/258) of patients. OAT patients showed a lower persistency of response (18/28 [64.3%]) and a higher persistency of nonresponse (57/63 [90.5%]) than omalizumab patients. Excellent and good GETE ratings in omalizumab-treated patients were reflected by improvements in exacerbation rates (P < 0.001), severe exacerbation rates (P = 0.023), hospitalizations (P = 0.003), total emergency visits (P = 0.026) and Asthma Control Questionnaire overall score (P < 0.001). CONCLUSION: Response to omalizumab, as assessed by a physician's GETE at 16 weeks, is an effective predictor of continuing persistent response to omalizumab for the majority of patients.

Palliative care concepts in respiratory disease.

Many respiratory diseases besides lung cancer are still not curable. There is an unmet need for palliative care, especially in non-malignant conditions. In this article we focus on symptomatic treatment of typical symptoms in respiratory disease beyond causal treatment.

Transesophageal endoscopic ultrasound-guided fine-needle aspiration for the mediastinal staging of extrathoracic tumors: a new perspective.

BACKGROUND: Several extrathoracic tumors metastasize to the mediastinum. Mediastinoscopy is the standard method to obtain tissue proof of mediastinal spread, but drawbacks are its invasiveness, requirement for general anesthesia and costs. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is indicated in lung cancer staging guidelines as a minimally invasive alternative for surgical staging. The diagnostic values in patients with suspected mediastinal metastases and various (previous) extrathoracic malignancies were assessed. PATIENTS AND METHODS: Consecutive patients with suspected mediastinal metastases (on computed tomography or positron emission tomography) and an (previous) extrathoracic malignancy underwent EUS-FNA. RESULTS: Seventy-five patients with current (n = 14) or previously diagnosed (n = 61) extrathoracic malignancies were evaluated. EUS-FNA detected mediastinal malignancies in 43 patients (57%) [metastases of extrathoracic tumors, n = 36 (48%); second malignancy (lung cancer), n = 7 (9%)]. Mediastinal metastases were found at subsequent surgical staging in seven patients or during follow-up (one patient). In seven patients, an alternative diagnosis was established. Sensitivity, specificity, accuracy and negative predictive value of EUS-FNA for mediastinal staging were 86%, 100%, 91% and 72%, respectively. CONCLUSION: EUS-FNA is a minimally invasive mediastinal staging method for patients with extrathoracic malignancies to confirm nodal metastatic spread and therefore may qualify as an alternative for surgical staging.