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Human leukocyte antigen (HLA) mismatches (MM) between donor and recipient lead to eplet MM (epMM) in lung transplantation (LTX), which can induce the development of de-novo donor-specific HLA-antibodies (dnDSA), particularly HLA-DQ-dnDSA. Aim of our study was to identify risk factors for HLA-DQ-dnDSA development. We included all patients undergoing LTX between 2012 and 2020. All recipients/donors were typed for HLA 11-loci. Development of dnDSA was monitored 1-year post-LTX. EpMM were calculated using HLAMatchmaker. Differences in proportions and means were compared using Chi2-test and Students' t-test. We used Kaplan-Meier curves with LogRank test and multivariate Cox regression to compare acute cellular rejection (ACR), chronic lung allograft dysfunction (CLAD) and survival. Out of 183 patients, 22.9% patients developed HLA-DQ-dnDSA. HLA-DQ-homozygous patients were more likely to develop HLA-DQ-dnDSA than HLA-DQ-heterozygous patients ( p = 0.03). Patients homozygous for HLA-DQ1 appeared to have a higher risk of developing HLA-DQ-dnDSA if they received a donor with HLA-DQB1*03:01. Several DQ-eplets were significantly associated with HLA-DQ-dnDSA development. In the multivariate analysis HLA-DQ-dnDSA was significantly associated with ACR ( p = 0.03) and CLAD ( p = 0.01). HLA-DQ-homozygosity, several high-risk DQ combinations and high-risk epMM result in a higher risk for HLA-DQ-dnDSA development which negatively impact clinical outcomes. Implementation in clinical practice could improve immunological compatibility and graft outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kleid, Walter, Moehnle, Wichmann, Kovács, Humpe, Schneider, Michel, Kneidinger, Irlbeck, Fertmann, Dick and Kauke.)

Background: The R-Scale-PF was proposed to evaluate the health-related quality of life (HRQoL) in patients with idiopathic pulmonary fibrosis (IPF). We generated a German version of the R-Scale-PF (GR-Scale), representing the first translation of the questionnaire into another language and assessed HRQoL longitudinally in various interstitial lung diseases (ILDs) using the R-Scale-PF scoring system at a specialized ILD centre., Methods: We have translated the questionnaire in accordance with the WHO translation guidelines and applied it to 80 ILD patients of our department, with follow-ups after 3-6 months, assessing its internal consistency, floor and ceiling effects, concurrent validity, known-groups validity, and its responsiveness to changes over time., Results: At baseline, all 80 patients completed the GR-Scale. In 70 patients (87.5%), follow-up data could be obtained after 4.43 ± 1.2 months. The GR-Scale demonstrated acceptable internal consistency (Cronbach's α 0.749) and slight floor effects. Concurrent validity analysis showed weak but significant correlations with forced vital capacity (FVC; r=-0.282 p = 0.011) and diffusion capacity for carbon monoxide (DLco; r=-0.254 p = 0.025). In the follow-up analysis, moderate correlations were found with FVC (r=-0.41 p < 0.001) and DLco (r=-0.445 p < 0.001). No significant difference in the total score was found between patients with IPF (n = 10) and with non-IPF ILDs (n = 70). The GR-Scale successfully discriminated between groups of varying disease severity based on lung function parameters and the need for long-term oxygen therapy (LTOT). Furthermore, it was able to distinguish between patients showing improvement, stability or decline of lung function parameters., Conclusion: Our prospective observational pilot study suggests that the GR-Scales is a simple and quick tool to measure HRQoL in patients with ILDs, thus providing an important additional information for the clinical assessment of ILD patients., Trial Registration: Our study was retrospectively registered in the German Clinical Trial Register (DRKS) on 02.11.2022 (DRKS-ID: DRKS00030599)., (© 2024. The Author(s).)

Background: Baseline lung allograft dysfunction (BLAD) is characterized by the failure to achieve normal baseline lung function after double lung transplantation (DLTX) and is associated with a high risk of mortality. In single lung transplant (SLTX) recipients, however, cutoff values and associated factors have not been explored. Here, we aimed to define BLAD in SLTX recipients, investigate its impact on allograft survival, and identify potential risk factors for BLAD in SLTX recipients., Methods: We performed a retrospective, single-center analysis of the LTX cohort of LMU Munich between 2010 and 2018. In accordance with DLTX cutoffs, BLAD in SLTX recipients was defined as failure to achieve percentage of forced expiratory volume in 1 s and percentage of forced vital capacity of >60% on 2 consecutive tests >3 wk apart. Survival analysis and regression analysis for potential predictors of BLAD were performed., Results: In a cohort of 141 SLTX recipients, 43% of patients met BLAD criteria. SLTX recipients with BLAD demonstrated impaired survival. Native lung hyperinflation was associated with BLAD in obstructive disease, whereas donor/recipient lung size mismatch was associated with BLAD in both obstructive and restrictive underlying diseases. Pulmonary function testing at 3 mo after lung transplantation predicted normal baseline lung function in SLTX recipients with obstructive lung disease., Conclusions: BLAD in SLTX recipients is as relevant as in DLTX recipients and should generally be considered in the follow-up of LTX recipients. Risk factors for BLAD differed between underlying obstructive and restrictive lung disease. A better understanding of associated factors may help in the development of preventive strategies., Competing Interests: This work was supported by the German Center of Lung Research (DZL). The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Candidate selection for lung transplantation (LuTx) is pivotal to ensure individual patient benefit as well as optimal donor organ allocation. The impact of coronary artery disease (CAD) on post-transplant outcomes remains controversial. We provide comprehensive data on the relevance of CAD for short- and long-term outcomes following LuTx and identify risk factors for mortality., Methods: We retrospectively analyzed all adult patients (≥ 18 years) undergoing primary and isolated LuTx between January 2000 and August 2021 at the LMU University Hospital transplant center. Using 1:1 propensity score matching, 98 corresponding pairs of LuTx patients with and without relevant CAD were identified., Results: Among 1,003 patients having undergone LuTx, 104 (10.4%) had relevant CAD at baseline. There were no significant differences in in-hospital mortality (8.2% vs. 8.2%, p > 0.999) as well as overall survival (HR 0.90, 95%CI [0.61, 1.32], p = 0.800) between matched CAD and non-CAD patients. Similarly, cardiovascular events such as myocardial infarction (7.1% CAD vs. 2.0% non-CAD, p = 0.170), revascularization by percutaneous coronary intervention (5.1% vs. 1.0%, p = 0.212), and stroke (2.0% vs. 6.1%, p = 0.279), did not differ statistically between both matched groups. 7.1% in the CAD group and 2.0% in the non-CAD group (p = 0.078) died from cardiovascular causes. Cox regression analysis identified age at transplantation (HR 1.02, 95%CI [1.01, 1.04], p < 0.001), elevated bilirubin (HR 1.33, 95%CI [1.15, 1.54], p < 0.001), obstructive lung disease (HR 1.43, 95%CI [1.01, 2.02], p = 0.041), decreased forced vital capacity (HR 0.99, 95%CI [0.99, 1.00], p = 0.042), necessity of reoperation (HR 3.51, 95%CI [2.97, 4.14], p < 0.001) and early transplantation time (HR 0.97, 95%CI [0.95, 0.99], p = 0.001) as risk factors for all-cause mortality, but not relevant CAD (HR 0.96, 95%CI [0.71, 1.29], p = 0.788). Double lung transplant was associated with lower all-cause mortality (HR 0.65, 95%CI [0.52, 0.80], p < 0.001), but higher in-hospital mortality (OR 2.04, 95%CI [1.04, 4.01], p = 0.039)., Conclusion: In this cohort, relevant CAD was not associated with worse outcomes and should therefore not be considered a contraindication for LuTx. Nonetheless, cardiovascular events in CAD patients highlight the necessity of control of cardiovascular risk factors and a structured cardiac follow-up., Competing Interests: Declarations. Ethical standards: All ethical standards were met in writing and submitting this correspondence. Conflicts of interest: The authors declare no conflict of interests related to the submitted work., (© 2024. The Author(s).)

Systemic anticancer therapies (SACTs) are the leading cause of drug-induced interstitial lung disease (ILD). As more novel SACTs become approved, the incidence of this potentially life-threatening adverse event (AE) may increase. Early detection of SACT-related ILD allows for prompt implementation of drug-specific management recommendations, improving the likelihood of AE resolution and, in some instances, widening the patient's eligibility for future cancer treatment options. ILD requires a diagnosis of exclusion through collaboration with the patient's multidisciplinary team to rule out other possible etiologies of new or worsening respiratory signs and symptoms. At Grade 1, ILD is asymptomatic, and thus the radiologist is key to detecting the AE prior to the disease severity worsening. Planned computed tomography scans should be reviewed for the presence of ILD in addition to being assessed for tumor response to treatment, and when ILD is suspected, a high-resolution computed tomography (HRCT) scan should be requested immediately. An HRCT scan, with < 2-mm slice thickness, is the most appropriate method for detecting ILD. Multiple patterns of ILD exist, which can impact patient prognosis. The four main patterns include acute interstitial pneumonia / acute respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, and non-specific interstitial pneumonia; their distinct radiological features, along with rarer patterns, are discussed here. Furthermore, HRCT is essential for following the course of ILD and might help to determine the intensity of AE management and the appropriateness of re-challenging with SACT, where indicated by drug-specific prescribing information. ILD events should be monitored closely until complete resolution. CRITICAL RELEVANCE STATEMENT: The incidence of potentially treatment-limiting and life-threatening systemic anticancer therapy-related interstitial lung disease (SACT-related ILD) events is likely increasing as more novel regimens become approved. This review provides best-practice recommendations for the early detection of SACT-related ILD by radiologists. KEY POINTS: Radiologists are crucial in detecting asymptomatic (Grade 1) ILD before severity/prognosis worsens. High-resolution computed tomography is the most appropriate method for detecting ILD. Drug-induced ILD is a diagnosis of exclusion, involving a multidisciplinary team. Familiarity with common HRCT patterns, described here, is key for prompt detection. Physicians should highlight systemic anticancer therapies (SACTs) with a known risk for interstitial lung diseases (ILD) on scan requisitions., (© 2024. The Author(s).)

A prospective observational study comparing mechanical power density (MP normalized to dynamic compliance) with traditional spontaneous breathing indexes (e.g., predicted body weight normalized tidal volume [VT/PBW], rapid shallow breathing index [RSBI], or the integrative weaning index [IWI]) for predicting prolonged weaning failure in 140 tracheotomized patients. We assessed the diagnostic accuracy of these indexes at the start and end of the weaning procedure using ROC curve analysis, expressed as the area under the receiver operating characteristic curve (AUROC). Weaning failure occurred in 41 out of 140 patients (29%), demonstrating significantly higher MP density (6156 cmH 2 O 2 /min [4402-7910] vs. 3004 cmH 2 O 2 /min [2153-3917], P < 0.01), lower spontaneous VT/PBW (5.8 mL*kg -1 [4.8-6.8] vs. 6.6 mL*kg -1 [5.7-7.9], P < 0.01) higher RSBI (68 min -1 *L -1 [44-91] vs. 55 min -1 *L -1 [41-76], P < 0.01) and lower IWI (41 L 2 /cmH 2 O*%*min*10 -3 [25-72] vs. 71 L 2 /cmH 2 O*%*min*10 -3 [50-106], P < 0.01) and at the end of weaning. MP density was more accurate at predicting weaning failures (AUROC 0.91 [95%CI 0.84-0.95]) than VT/PBW (0.67 [0.58-0.74]), RSBI (0.62 [0.53-0.70]), or IWI (0.73 [0.65-0.80]), and may help clinicians in identifying patients at high risk for long-term ventilator dependency., (© 2024. The Author(s).)

Background: Benralizumab reduces exacerbations and long-term oral glucocorticosteroid (OCS) exposure in patients with severe eosinophilic asthma. In patients with eosinophilic granulomatosis with polyangiitis (EGPA), uncontrolled symptoms and exacerbations of asthma and chronic rhinosinusitis (CRS) are important reasons for continued OCS therapies. We aimed to describe outcomes of patients with severe asthma and EGPA treated with benralizumab in real-life., Methods: We retrospectively analyzed adult patients from the Severe Asthma Unit at LMU Munich diagnosed with severe asthma and EGPA treated with benralizumab, differentiating two groups: Group A, patients with a stable daily OCS dose and diagnosis of EGPA >6 months ago; and Group B, patients treated with high-dose daily OCS due to recent diagnosis of EGPA <6 months ago. We compared outcome parameters at baseline and 12 months after initiation of benralizumab, including respiratory exacerbations, daily OCS dose, and lung function., Results: Group A included 17 patients, all receiving OCS therapy and additional immunosuppressants; 15 patients (88%) continued benralizumab for more than 12 months, demonstrating a significant reduction in daily OCS dose and exacerbations while FEV1 increased. Group B included 9 patients, all with high-dose daily OCS and some receiving cyclophosphamide pulse therapy for life-threatening disease. Benralizumab addition during induction was well tolerated. A total of 7/9 (78%) continued benralizumab for more than 12 months and preserved EGPA remission at the 12-month timepoint., Conclusion: In this real-life cohort of patients with severe asthma and EGPA, benralizumab initiation during remission maintenance reduced respiratory exacerbations and daily OCS dose. Benralizumab initiation during remission induction was associated with a high rate of clinical EGPA remission., Competing Interests: CM reports speaker and/or consultancy fees from Sanofi, outside of the submitted work. PM reports speaker and/or consultancy fees from AstraZeneca, ResMed, Insmed, Vertex, all outside of the submitted work. US has received consulting fees from Ablynx, Alexion, and Vifor Pharma and reports research support from Vifor Pharma, Ablynx/Sanofi, and Alexion, all outside the submitted work. UG received speaker honoraria from AstraZeneca outside of the submitted work. HSK served as consultant and advisor or review panel member for AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celgene, Gilead, Galapagos, Hexal Sandoz, Janssen-Cilag, Elli Lilly, Medac, MSD, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, all outside the submitted work. JB reports speaker and/or consultancy fees from AstraZeneca, GSK, Novartis, Sanofi, all outside of the submitted work. NK reports speaker and/or consultancy fees from AstraZeneca and GSK, all outside of the submitted work. KM reports speaker and/or consultancy fees from AstraZeneca, Chiesi, GSK, Novartis, Sanofi, all outside of the submitted work. The author report no other conflicts of interest in this work., (© 2024 Mümmler et al.)

Background: Right ventricular (RV) dysfunction in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) has long been disregarded. We aimed to assess the predictive value of RV to pulmonary artery coupling (RV/PAc), defined as tricuspid annular plane systolic excursion to systolic pulmonary artery pressure, on mortality in different flow types of AS after TAVI., Methods: All patients undergoing TAVI for AS at our centre between 2018 and 2020 were assessed; 862 patients were analysed. The cohort was dichotomized using a ROC analysis (cut-off 0.512 mm/mmHg), into 429 patients with preserved and 433 patients with reduced RV/PAc., Results: Reduced RV/PAc was associated with male sex and a higher rate of comorbidities. Short-term VARC-3 endpoints and NYHA classes at follow-up were comparable. Reduced RV/PAc was associated with higher 2-year all-cause mortality (35.0% [30.3-39.3%] vs. 15.4% [11.9-18.7%], hazard ratio 2.5 [1.9-3.4], p < 0.001). Cardiovascular mortality was almost tripled. Results were consistent after statistical adjustment and in a multivariate model. Sub-analyses of AS flow types revealed lower RV/PAc in classical and paradoxical low-flow low-gradient AS, with the majority having reduced RV/PAc (74% and 59%). RV/PAc retained its predictive value in these subgroups., Conclusions: RV dysfunction defined by low RV/PAc is a strong mortality predictor after TAVI independent of flow group. It should be incorporated in future TAVI risk assessment., (© 2024. The Author(s).)

Due to immunosuppression, transplant recipients are at higher risk of infections with SARS-CoV-2 and worse clinical outcomes than immunocompetent hosts. Furthermore, lung transplant patients represent a special group among solid organ recipients, since pneumonia is the main manifestation of COVID-19. However, data on the course of disease and the changes in morbidity and mortality during the course of the pandemic are limited. In our pulmonary rehabilitation clinic, we treat patients shortly after lung transplant as well as long-term transplant patients. Over the last almost 4 years of pandemic, we witnessed several COVID-19 infections in lung transplant patients in our clinic as well as patients who acquired an infection beforehand. In this paper, we aim at retrospectively describing a series of recent COVID-19 cases in our clinic, looking at the clinical course of disease and outcomes in lung transplant patients.

Background: Monoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months., Methods: 280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published "Biologic Asthma Response Score" (BARS)., Results: All biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months., Conclusions: All biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment., (© 2024. The Author(s).)

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Lung transplantation is currently the gold standard treatment for end-stage lung diseases. Advances in the preservation of donor lungs, the surgical technique and immunosuppressive therapy have led to lung transplantation now being a routine procedure. Nevertheless, the shortage of donor organs, the acute and particularly chronic lung allograft dysfunction (CLAD) still represent major challenges even in experienced centers. Research in this area is still necessary to improve the long-term survival of lung recipients., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, their specific activation states and phenotypic trajectories during injury and repair have remained unclear., Methods: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in IPF patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to TGFβ1., Measurements and Main Results: We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21 -Cre lineage positive and negative cells. Sfrp1 + cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1 + transitional fibroblasts and Cthrc1 + myofibroblasts. TGFβ1 downregulated SFRP1 in non-invasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss of function studies we showed that SFRP1 modulates TGFβ1 induced fibroblast invasion and RHOA pathway activity., Conclusions: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1 driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.

Eosinophilic inflammation is a hallmark of asthma, and blood eosinophilia has been established as a biomarker for phenotyping asthma and predicting the response to anti-IL5 treatments. Although parasitic infections are rare in European adults, they remain an important differential diagnosis for blood eosinophilia. We present three patients with both domestic parasitic infections and asthma to raise awareness of the potential challenge of eosinophilia and to provide experience in the management of parasitic infections in the setting of planned or ongoing anti-IL5 treatment. One, a patient from Croatia with moderate asthma but severe blood eosinophilia had an underlying Strongyloides stercoralis infection, with positive stool cultures. Second, a patient with severe allergic asthma and gastrointestinal symptoms had a positive S. stercoralis titer in serology with a clinical response to treatment with ivermectin. Third, a patient with severe nonallergic eosinophilic asthma and eosinophilic granulomatosis with polyangiitis (EGPA) showed an increasing hepatic tumour under anti-IL5-receptor therapy. Positive serology confirmed the diagnosis of Echinococcus multilocularis , and albendazole therapy was initiated. Anti-IL5 therapies were safely started (Patient 2) or resumed (Patient 3) after the initiation of antiparasitic treatment. Screening for parasitic infections is useful in cases of hypereosinophilia, extrapulmonary symptoms or stay in endemic regions., Competing Interests: KM received speaker fees from AstraZeneca, GSK, Novartis, and Sanofi, all outside of the submitted work., (© 2023 Barnikel et al.)

Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance of ≤ 5 Wood units (WU). Both the non-severe (PVR ≤ 5 WU) and much more the severe PH (PVR > 5 WU) have an unfavorable prognosis.If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly.For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended - if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a "pulmonary vascular" phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO < 45 % of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population., Competing Interests: M.H.: Honorare für Vortrags- und Beratertätigkeiten von AstraZeneca, Janssen und MSD. Reisekosten von Janssen. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.K.E.Z.: Reisekosten und Vortragstätigkeiten von Fa. MSD, Janssen und Ferrer. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.N.S.: Honorare für Berater- und Vortragstätigkeiten von MSD und Janssen. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.S.U.: Forschungsgelder vom Schweizerischen Nationalfond, der Lungenliga Schweiz, der Lunge Zürich, der Emdo Foundation, von Janssen SA, Orpha Swiss. Reisekosten und Vortragstätigkeiten von Janssen SA, Orpha Swiss, MSD und Novartis, alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.M.H.: Beratungshonorare: Actelion, Bayer Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, MSD, Pfizer. Honorare für Vorträge von: Actelion, AstraZeneca, Bayer HealthCare, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daichi Sankyo, Janssen, MSD, Pfizer, Santis.T.K.: Honorare für Vortragstätigkeiten und Reisekostenübernahme von AstraZeneca, Berlin Chemie, Janssen und MSD. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.V.F.: Honorare für Vortragstätigkeiten und Reisekostenübernahme von Boehringer Ingelheim, BMS, Chiesi, Janssen, MSD, alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.M.H.: keineC.N.: Honorare für Vortrags- und Beratertätigkeiten von AstraZeneca, Janssen und MSD. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.J.R.: keineS.H.: Zuwendungen von Janssen, Bayer und MSD, die in keinem Zusammenhang mit dieser Arbeit stehen.D.S.: Vortrags- und Beratungshonorare und/oder Forschungsunterstützung von AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, DFG, BMBF. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.N.K.: erhielt finanzielle Zuwendungen von Janssen, Ferrer, Bayer und MSD, die in keinem Zusammenhang mit dieser Arbeit stehen.J.B.: Honorare für Vorträge und Beratertätigkeit von AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Ferrer, Novartis, Roche, and Sanofi-Genzyme. Für Tätigkeiten im Rahmen von Data Monitoring and Safety Boards erhielt er Honorare von Actelion und Galapagos. Es besteht kein Zusammenhang mit der vorliegenden Publikation., (Thieme. All rights reserved.)

Autoimmunity plays a role in certain types of lung fibrosis, notably connective tissue disease-associated interstitial lung disease (CTD-ILD). In idiopathic pulmonary fibrosis (IPF), an incurable and fatal lung disease, diagnosis typically requires clinical exclusion of autoimmunity. However, autoantibodies of unknown significance have been detected in IPF patients. We conducted computational analysis of B cell transcriptomes in published transcriptomics datasets and developed a proteomic Differential Antigen Capture (DAC) assay that captures plasma antibodies followed by affinity purification of lung proteins coupled to mass spectrometry. We analyzed antibody capture in two independent cohorts of IPF and CTL-ILD patients over two disease progression time points. Our findings revealed significant upregulation of specific immunoglobulins with V-segment bias in IPF across multiple cohorts. We identified a predictive autoimmune signature linked to reduced transplant-free survival in IPF, persisting over time. Notably, autoantibodies against thrombospondin-1 were associated with decreased survival, suggesting their potential as predictive biomarkers., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Purpose: Lung transplant (LTx) recipients are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). The aim of the study was to assess the outcome of patients receiving pre-exposure prophylaxis (PrEP) with tixagevimab and cilgavimab after LTx., Methods: All LTx recipients with outpatient visits from February 28th to October 31st, 2022 at two German centers were included. Baseline characteristics were recorded and patients followed until November 30rd, 2022. Infections with SARS-CoV-2, disease severity, and COVID-19-associated death were compared between patients with and without PrEP., Results: In total, 1438 patients were included in the analysis, and 419 (29%) received PrEP. Patients receiving PrEP were older and earlier after transplantation, had lower glomerular filtration rates, and lower levels of SARS-CoV-2-S antibodies. In total, 535 patients (37%) developed SARS-CoV-2 infection during a follow-up of median of 209 days. Fewer infections occurred in patients with PrEP during the study period (31% vs. 40%, p = 0.004). Breakthrough SARS-CoV-2 infections after PrEP occurred in 77 patients (19%). In total, 37 infections (8%) were severe or critical. No difference in severity of COVID-19 was observed between patients with and without PrEP. There were 15 COVID-19-associated deaths (n = 1 after PrEP). Compared to matched controls, there was a non-significant difference towards a lower risk for moderate to critical COVID-19 (p 0.184)., Conclusion: The number of SARS-CoV-2 infections was lower in LTx recipients with PrEP. Despite being at higher risk for worse outcome severity of COVID-19 and associated mortality were similar in patients with and without PrEP., (© 2023. The Author(s).)

Prolonged mechanical ventilation (PMV) after lung transplantation poses several risks, including higher tracheostomy rates and increased in-hospital mortality. Mechanical power (MP) of artificial ventilation unifies the ventilatory variables that determine gas exchange and may be related to allograft function following transplant, affecting ventilator weaning. We retrospectively analyzed consecutive double lung transplant recipients at a national transplant center, ventilated through endotracheal tubes upon ICU admission, excluding those receiving extracorporeal support. MP and derived indexes assessed up to 36 h after transplant were correlated with invasive ventilation duration using Spearman's coefficient, and we conducted receiver operating characteristic (ROC) curve analysis to evaluate the accuracy in predicting PMV (>72 h), expressed as area under the ROC curve (AUROC). PMV occurred in 82 (35%) out of 237 cases. MP was significantly correlated with invasive ventilation duration (Spearman's ρ = 0.252 [95% CI 0.129-0.369], p < 0.01), with power density (MP normalized to lung-thorax compliance) demonstrating the strongest correlation ( ρ = 0.452 [0.345-0.548], p < 0.01) and enhancing PMV prediction (AUROC 0.78 [95% CI 0.72-0.83], p < 0.01) compared to MP (AUROC 0.66 [0.60-0.72], p < 0.01). Mechanical power density may help identify patients at risk for PMV after double lung transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ghiani, Kneidinger, Neurohr, Frank, Hinske, Schneider, Michel and Irlbeck.)

Background: Recently, criteria for evaluation of response to biologics have been proposed and the concept of clinical remission has gained attention as a possible goal even in severe asthma., Objective: To analyze the response and remission in the German Asthma Net severe asthma registry cohort., Methods: We included adults not using a biologic at baseline (V0) and compared patients treated between V0 and 1-year visit (V1) without using a biologic (group A) to patients starting with a biologic after V0 and continuing it up to V1 (group B). We applied the Biologics Asthma Response Score to quantify composite response in good, intermediate, or insufficient. We defined clinical remission (R) as absence of significant symptoms (Asthma Control Test score ≥ 20 at V1) in the absence of exacerbations and oral corticosteroid therapy., Results: Group A included 233 and group B 210 patients, the latter receiving omalizumab (n = 33), mepolizumab (n = 40), benralizumab (n = 81), reslizumab (n = 1), or dupilumab (n = 56). At baseline, group B had less often an allergic phenotype (35.2% vs 41.6%), lower Asthma Control Test score (median, 12 vs 14), more exacerbations in the past year (median, 3 vs 2), and more often high-dose inhaled corticosteroid treatment (71.4% vs 51.5%) than group A. After 1 year of treatment, rates of response (good: 61.4% vs 34.8%; intermediate: 26.7% vs 42.9%; insufficient: 11.9% vs. 22.3%) and/or clinical remission (37.6% vs 17.2%) were higher in group B than in group A., Conclusions: Despite more severe asthma at baseline, patients treated with biologics had a markedly higher probability of achieving good clinical response and/or remission than patients treated without biologics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular matching is a new approach for virtual histocompatibility testing in organ transplantation. The aim of our study was to analyze whether the risk for de novo donor-specific HLA antibodies (dnDSA) after lung transplantation (LTX) can be predicted by molecular matching algorithms (MMA) and their combination. In this retrospective study we included 183 patients undergoing LTX at our center from 2012-2020. We monitored dnDSA development for 1 year. Eplet mismatches (epMM) using HLAMatchmaker were calculated and highly immunogenic eplets based on their ElliPro scores were identified. PIRCHE-II scores were calculated using PIRCHE-II algorithm (5- and 11-loci). We compared epMM and PIRCHE-II scores between patients with and without dnDSA using t-test and used ROC-curves to determine optimal cut-off values to categorize patients into four groups. We used logistic regression with AIC to compare the predictive value of PIRCHE-II, epMM, and their combination. In total 28.4% of patients developed dnDSA (n = 52), 12.5% class I dnDSA (n = 23), 24.6% class II dnDSA (n = 45), and 8.7% both class II and II dnDSA (n = 16). Mean epMMs (p-value = 0.005), mean highly immunogenic epMMs (p-value = 0.003), and PIRCHE-II (11-loci) (p = 0.01) were higher in patients with compared to without class II dnDSA. Patients with highly immunogenic epMMs above 30.5 and PIRCHE-II 11-loci above 560.0 were more likely to develop dnDSA (31.1% vs. 14.8%, p-value = 0.03). The logistic regression model including the grouping variable showed the best predictive value. MMA can support clinicians to identify patients at higher or lower risk for developing class II dnDSA and might be helpful tools for immunological risk assessment in LTX patients., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Immunosuppressants and antifibrotics are currently used to treat patients with various interstitial lung diseases, which may undergo lung transplantation (LTx). The retrospective study aimed to evaluate the potential effects of therapeutic regimen on the perioperative course in patients with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF) undergoing LTx. All patients with IPF and PPF undergoing LTx between January 2014 and December 2021 were included. We retrospectively screened for previous use of immunosuppressants and antifibrotic therapy. We analyzed perioperative courses, short-term outcomes, and safety retrospectively. In total, 286 patients with diagnosis of IPF or PPF were analyzed. According to the treatment regimen before LTx, the study cohort was divided into four groups and compared. No differences between antifibrotic monotherapy, combined antifibrotic and immunosuppressive therapy with regard to postoperative complications were observed. Length of mechanical ventilation was shorter in patients with antifibrotics prior to LTx. Pretreatment with antifibrotic monotherapy and a combination of antifibrotic drugs with immunosuppressive therapy, lower body mass index (BMI) and lower blood loss, were independently associated with primary graft dysfunction grades 0-3 72 hours after LTx ( p < 0.001). Finally, patients with antifibrotic monotherapy developed significantly less de novo donor-specific antibodies (DSA) ( p = 0.009). Higher intraoperative blood loss, etiology of interstitial lung disease (ILD) and older age were independently associated with shorter survival after LTx. Use of antifibrotic monotherapy and a combination of antifibrotic drugs with immunosuppressive therapy in IPF/PPF patients undergoing LTx, proved to be safe and might lead to beneficial effects after LTx.

Pulmonary hypertension (PH) is a known and life limiting complication of preterm born young adults with bronchopulmonary dysplasia (BPD), ultimately leading to progressive right ventricular (RV) failure. Prognosis remains poor, especially in patients unresponsive to modern vasoactive pharmacotherapy. Therefore, lung transplantation presents the treatment of choice to avert cardiac failure. With limited donor organ availability and long waiting times, the implantation of a paracorporeal lung assist device (PLAD) is a way to bridge the patient as an alternative to veno-arterial ECMO. Herein, we present the case of a prematurely born 23-year-old female, who developed severe PH due to BPD and consequently experienced therapy refractory RV failure. Urgent PLAD implantation was performed and the patient successfully underwent double-lung transplantation after 215 days of PLAD support. No major PLAD-associated complications occurred and full recovery of RV function could be observed after double-lung transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. SM and TV declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Michel, Hanuna, Pattathu, Pabst von Ohain, Schneider, Kauke, Kneidinger, Behr, Milger, Barton, Veit, Kamla, Mueller, Dzieciol, Christen, Irlbeck, Tomasi, Abicht, Scheiermann, Feuerecker, Dalla-Pozza, Fischer, Jakob, Hermann, Haas, Hagl and Hörer.)

Purpose: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is currently the major threat for immunocompromised individuals. The course of COVID-19 in lung transplant recipients in the Omicron era remains unknown. The aim of the study was to assess outcome and associated factors in lung transplant recipients in a German-wide multicenter approach., Methods: All affected individuals from January 1st to March 20th, 2022 from 8 German centers during the Omicron wave were collected. Baseline characteristics and antiviral measures were associated with outcome., Results: Of 218 patients with PCR-proven SARS-CoV-2 infection 166 patients (76%) received any early (< 7 days) antiviral therapy median 2 (interquartile range 1-4) days after symptom onset. Most patients received sotrovimab (57%), followed by remdesivir (21%) and molnupiravir (21%). An early combination therapy was applied in 45 patients (21%). Thirty-four patients (16%) developed a severe or critical disease severity according to the WHO scale. In total, 14 patients (6.4%) died subsequently associated with COVID-19. Neither vaccination and antibody status, nor applied treatments were associated with outcome. Only age and glomerular filtration rate < 30 ml/min/1.73m 2 were independent risk factors for a severe or critical COVID-19., Conclusion: COVID-19 due to Omicron remains an important threat for lung transplant recipients. In particular, elderly patients and patients with impaired kidney function are at risk for worse outcome. Prophylaxis and therapy in highly immunocompromised individuals need further improvement., (© 2022. The Author(s).)

Physical activity limitations and cough are common in patients with interstitial lung disease (ILD), potentially leading to reduced health-related quality of life. We aimed to compare physical activity and cough between patients with subjective, progressive idiopathic pulmonary fibrosis (IPF) and fibrotic non-IPF ILD. In this prospective observational study, wrist accelerometers were worn for seven consecutive days to track steps per day (SPD). Cough was evaluated using a visual analog scale (VAS cough ) at baseline and weekly for six months. We included 35 patients (IPF: n = 13; non-IPF: n = 22; mean ± SD age 61.8 ± 10.8 years; FVC 65.3 ± 21.7% predicted). Baseline mean ± SD SPD was 5008 ± 4234, with no differences between IPF and non-IPF ILD. At baseline, cough was reported by 94.3% patients (mean ± SD VAS cough 3.3 ± 2.6). Compared to non-IPF ILD, patients with IPF had significantly higher burden of cough ( p = 0.020), and experienced a greater increase in cough over six months ( p = 0.009). Patients who died or underwent lung transplantation ( n = 5), had significantly lower SPD ( p = 0.007) and higher VAS cough ( p = 0.047). Long-term follow up identified VAS cough (HR: 1.387; 95%-CI 1.081-1.781; p = 0.010) and SPD (per 1000 SPD: HR 0.606; 95%-CI: 0.412-0.892; p = 0.011) as significant predictors for transplant-free survival. In conclusion, although activity didn't differ between IPF and non-IPF ILD, cough burden was significantly greater in IPF. SPD and VAS cough differed significantly in patients who subsequently experienced disease progression and were associated with long-term transplant-free survival, calling for better acknowledgement of both parameters in disease management.

The SARS-CoV-2 pandemic had a tremendous impact on diagnosis and treatment of interstitial lung diseases (ILD). Especially in the early phase of the pandemic, when the delta variant was prevailling, a huge number of viral pneumonias were observed, which worsened pre-existing, triggered de novo occurence or discovery of previously subclincal interstitial lung diseases. The effect of SARS-CoV-2 infection - without or with accompanying viral pneumonia - on the further development of pre-existing ILD as well of new pulmonary inflitrates and consolidiations is difficult to predict and poses a daily challenge to interdisciplinary ILD boards. This position paper of the German Respiratory Society (DGP e.V.) provides answers to the most pressing questions based on current knowledge., Competing Interests: JB erhielt Honorare für Vortragstätigkeit und Beratung von AstraZeneca, Boehringer-Ingelheim, Ferrer, Galapagos, Novartis, Roche und Sanofi/Gemzyme. MPB hat Honorare für Vorträge, Beratung und Kongresssponsoring von Boehringer-Ingelheim und Roche erhalten. TGB erhielt Honorare für Vortragstätigkeit und Beratung von Astra-Zeneca, Boehringer-Ingelheim, Johnson & Johnson, MSD, Pfizer und Roche (ohne Zusammenhang mit dieser Arbeit). FB erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Sanofi, Fujirebio und Fibrogen. JD erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Parexel und Astrazeneca. SG erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Berlin Chemie, Novartis, Astra Zeneca. LH erhielt Honorare für Vortragstätigkeit und Beratung für Boehringer-Ingelheim und Roche. NK hat keine Interessenkonflikte. DK erhielt Honorare für Vortragstätigkeit und Beratung sowie finanzielle Unterstützung bei Kongressbesuchen von Boehringer Ingelheim und Roche. AP erhielt Vortragshonorare von Boehringer Ingelheim, Novartis, Roche, Pfizer und Chiesi und Beratungshonorare von Boehringer Ingelheim, Novartis, Amgen, und Astra-Zeneca. Forschungsprojekte am Fraunhofer ITEM bestehen mit Boehringer Ingelheim, Novartis, Chiesi, AdAlta, Alentis und AiThera. ESP erhielt Honorare für Vortragstätigkeit von Boehringer-Ingelheim, Roche und Bristol-Myers-Squibb. HS hat keine Interessenskonflikte. HW hat Beratungs-/Vortragshonorare von Astra Zeneca, Allergopharma, Boehringer Ingelheim, Bioprojet, GSK, Inspire Medical, Jazz Pharma, Novartis, ResMed, Sanofi, VitalAire sowie Vivisol erhalten. MK erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Ferrer, Galapagos., (Thieme. All rights reserved.)

SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development., Competing Interests: Declaration of competing interest The authors declare no conflict of interest apart from Clemens Scherer, who received speaker honoraria from AstraZeneca, outside the submitted work. All authors were involved in the decision to publish and reviewed the article before submission. The authors declare no conflict of interest apart from Clemens Scherer, who received speaker honoraria from AstraZeneca, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Posterior reversible encephalopathy syndrome is a rare neurologic complication that can occur under immunosuppressive therapy with CNI after organ transplantation., Methods: We retrospectively reviewed medical records of 545 patients who underwent lung transplantation between 2012 and 2019. Within this group, we identified 30 patients with neurological symptoms typical of PRES and compared the characteristics of patients who were diagnosed with PRES (n = 11) to those who were not (n = 19)., Results: The incidence of PRES after lung transplantation was 2%. Notably, 73% of the patients with PRES were female and the mean age was 39.2. Seizure (82% vs. 21%, p = .002) was the most common neurological presentation. The risk of developing PRES was significantly associated with age (OR = .92, p < .0001) and having cystic fibrosis (CF) (OP = 10.1, p < .0001). Creatinine level (1.9 vs. 1.1 mg/dl, p = .047) and tacrolimus trough level (19.4 vs. 16.5 ng/ml, p = .048) within 1 week prior to neurological symptoms were significantly higher in patients with PRES., Conclusion: Renal insufficiency and high tacrolimus levels are associated with PRES. A change of immunosuppressive drug should be done after confirmed PRES diagnosis or immediately in case of severe neurological dysfunction to improve neurological outcomes and minimize the risk of early allograft rejection., (© 2022 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Evidence suggests differences in ventilation efficiency and respiratory mechanics between early COVID-19 pneumonia and classical acute respiratory distress syndrome (ARDS), as measured by established ventilatory indexes, such as the ventilatory ratio (VR; a surrogate of the pulmonary dead-space fraction) or mechanical power (MP; affected, e.g., by changes in lung-thorax compliance)., Objectives: The aim of this study was to evaluate VR and MP in the late stages of the disease when patients are ready to be liberated from the ventilator after recovering from COVID-19 pneumonia compared to respiratory failures of other etiologies., Design: A retrospective observational cohort study of 249 prolonged mechanically ventilated, tracheotomized patients with and without COVID-19-related respiratory failure., Methods: We analyzed each group's VR and MP distributions and trajectories [repeated-measures analysis of variance (ANOVA)] during weaning. Secondary outcomes included weaning failure rates between groups and the ability of VR and MP to predict weaning outcomes (using logistic regression models)., Results: The analysis compared 53 COVID-19 cases with a heterogeneous group of 196 non-COVID-19 subjects. VR and MP decreased across both groups during weaning. COVID-19 patients demonstrated higher values for both indexes throughout weaning: median VR 1.54 versus 1.27 ( p  < 0.01) and MP 26.0 versus 21.3 Joule/min ( p  < 0.01) at the start of weaning, and median VR 1.38 versus 1.24 ( p  < 0.01) and MP 24.2 versus 20.1 Joule/min ( p  < 0.01) at weaning completion. According to the multivariable analysis, VR was not independently associated with weaning outcomes, and the ability of MP to predict weaning failure or success varied with lung-thorax compliance, with COVID-19 patients demonstrating consistently higher dynamic compliance along with significantly fewer weaning failures (9% versus 30%, p  < 0.01)., Conclusion: COVID-19 patients differed considerably in ventilation efficiency and respiratory mechanics among prolonged ventilated individuals, demonstrating significantly higher VRs and MP. The differences in MP were linked with higher lung-thorax compliance in COVID-19 patients, possibly contributing to the lower rate of weaning failures observed.

Background: Subjects with obesity show an increased prevalence of airway obstruction but it is not clear in each case whether this reflects genuine lung disease. Via intentional increase in end-expiratory lung volume we studied the detection of obesity-induced airway obstruction in lung-healthy obese subjects., Methods: The primary study population comprised 66 lung-healthy obese subjects and 23 normal weight subjects. Measurements were performed in a body plethysmograph allowing for recording and quantification of breathing loops in terms of specific airway resistance at both normal and intentionally elevated end-expiratory lung volume. The change in volume was documented by a shutter maneuver., Results: The voluntary increase of lung volume led to a significant reduction of expiratory airway resistance in 11 of the 66 obese subjects. This reduction could be quantified by a change of total expiratory resistance (sRtEX) of >1 kPa*s but was also clearly visible in the breathing loops. sRtEX showed the largest change among all resistance parameters. The loops of normal weight subjects remained virtually unaffected by the change in lung volume. Moreover, those of 5 obese patients with COPD who were measured for comparison partially showed a reduction of resistance but airway obstruction remained., Conclusion: The proposed breathing maneuver was simple to perform and allowed for a quantitative and qualitative detection of obesity-induced airway obstruction. This might help in reducing the likelihood of misdiagnosis and overtreatment of obese patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Positive bronchodilator responsiveness (BDR) (change in forced expiratory volume in 1 second [ΔFEV 1 ] ≥ +200 mL and ≥ +12%) after inhalation of a short-acting beta-2 agonist has been an inclusion criterion in licensing trials of anti-interleukin 5/anti-interleukin 5 receptor alpha (anti-IL-5/anti-IL-5Rα) biologics in severe asthma. However, in clinical practice, patients with severe uncontrolled asthma frequently show a negative BDR., Objective: To investigate whether the response to anti-IL5/anti-IL5Rα therapies differs between patients with positive and negative BDR at baseline., Methods: Retrospective multicenter analysis of treatment outcomes in patients with severe asthma receiving anti-IL-5/anti-IL-5Rα stratified for baseline BDR., Results: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL-5/anti-IL-5Rα treatment, FEV 1 improved significantly in both groups compared with baseline (P < .0001), with no significant difference between patients with positive and negative BDR (ΔFEV 1  +493 mL vs +306 mL; P = .06). Forced vital capacity (FVC) increased (ΔFVC: +85 mL vs +650 mL; P < .01) and residual volume (RV) decreased (ΔRV +113 mL vs -307 mL; P < .01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; P = .7), reduction of exacerbation rate (Δexacerbations 0 vs -2; P = .07), continuous oral corticosteroids (OCS) use (Δpatients on OCS -35% vs -39%; P = .99) and improvement of Asthma Control Test (ACT) score (ΔACT 6 vs 5; P = .7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive versus negative BDR with response parameters., Conclusions: Both groups improved following treatment with similar responses concerning reduction of OCS therapy, exacerbations, and improvement of symptom control. Pulmonary function also improved in both groups during anti-IL-5/anti-IL-5Rα treatment, with differences in response patterns noted., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for &gt;90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections., Competing Interests: Declaration of Competing Interest O.M.M is a consultant for AbbVie Deutschland GmbH, for PARI Pharma GmbH and an advisory board member for Coriolis Pharma GmbH., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Lung transplantation (LTx) can be considered for selected patients suffering from COVID-19 acute respiratory distress syndrome (ARDS). Secondary sclerosing cholangitis in critically ill (SSC-CIP) patients has been described as a late complication in COVID-19 ARDS survivors, however, rates of SSC-CIP after LTx and factors predicting this detrimental sequela are unknown., Methods: This retrospective analysis included all LTx performed for post-COVID ARDS at 8 European LTx centers between May 2020 and January 2022. Clinical risk factors for SSC-CIP were analyzed over time. Prediction of SSC-CIP was assessed by ROC-analysis., Results: A total of 40 patients were included in the analysis. Fifteen patients (37.5%) developed SSC-CIP. GGT at the time of listing was significantly higher in patients who developed SSC-CIP (median 661 (IQR 324-871) vs 186 (109-346); p = 0.001). Moreover, higher peak values for GGT (585 vs 128.4; p < 0.001) and ALP (325 vs 160.2; p = 0.015) were found in the 'SSC' group during the waiting period. Both, GGT at the time of listing and peak GGT during the waiting time, could predict SSC-CIP with an AUC of 0.797 (95% CI: 0.647-0.947) and 0.851 (95% CI: 0.707-0.995). Survival of 'SSC' patients was severely impaired compared to 'no SSC' patients (1-year: 46.7% vs 90.2%, log-rank p = 0.004)., Conclusions: SSC-CIP is a severe late complication after LTx for COVID-19 ARDS leading to significant morbidity and mortality. GGT appears to be a sensitive parameter able to predict SSC-CIP even at the time of listing., Competing Interests: Disclosure statement None of the authors have any relevant conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The interstitial lung diseases ILDs are a heterogeneous group of diseases that often lead to progressive fibrosis of the lungs with corresponding functional impairment. With nintedanib, a tyrosinkinase inhibitor and angiokinase inhibitor, as well as pirfenidone, which unfolds its effect among other things by inhibiting the transforming growth factor β, there are currently 2 approved antifibrotic drugs. In the rapidly progressing idiopathic pulmonary fibrosis IPF, the antifibrotic drugs nintedanib and pirfenidone have been established and approved in therapy for several years. The initiation of antifibrotic therapy should be carried out early after diagnosis by multidisciplinary discussion (MDD). In systemic scleroderma with lung involvement nintedanib should be used in the case of relevant fibrosis in addition to immunosuppressive therapy. Recently, nintedanib has also become a new option for the treatment of progressive fibrosing ILDs (PF-ILDs). This describes the course of various disease entities such as connective tissue disease associated ILDs (CTD-ILDs), fibrosing hypersensitivity pneumonitis or fibrosing courses of non-IPF idiopathic interstitial pneumonitis (non-IPF IIPs) that have a corresponding fibrose-related worsening of respiratory symptoms, a deterioration of lung-functioning parameters or a disease progression in CT. Although pirfenidone also shows positive signals for this group of patients in some selected studies, its use in PF-ILD is not yet recommended. In particular, gastrointestinal side effects can occur under therapy with antifibrotic drugs and require a long-term close interdisciplinary connection of patients., Competing Interests: Jürgen Behr erhielt Honorare für Beratung von Actelion, Biogen, BMS, Boehringer-Ingelheim, Galapagos, Roche, Sanofi-Genzyme; er erhielt Honorare für Vorträge von Astra-Zeneca, Boehringer-Ingelheim, Ferrer, Novartis, Roche; er ist Leiliniensprecher der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V. und Leiter der Leitliniengruppe für interstitielle Lungenerkrankungen.Nikolaus Kneidinger erklärt dass er in den letzten 3 Jahren Vortragshonorare von Roche und Boehringer Ingelheim erhalten hat., (Thieme. All rights reserved.)

Interstitial lung diseases (ILD) are etiologically heterogeneous with unknown and known causes like rheumatologic systemic diseases differing in their therapeutic and prognostic consequences. In consensus between pulmonologists, rheumatologists, radiologists, and pathologists, we developed practical instructions for ILD diagnosis in rheumatologic systemic diseases, in particular because ILD can present in early stages of rheumatic systemic diseases. ILD diagnosis is based on clinical assessment results including a detailed medical history, physical examination, focused laboratory tests, radiology with a high-resolution computed tomography, lung function, and histopathology also to differentiate it from cardiac and infection associated lung diseases. The ILD diagnosis is made in a multidisciplinary discussion leading to therapeutic and prognostic consequences. The occurrence of acute exacerbations is especially critical. They are often the causes for ILD progression and are associated with considerable mortality., Competing Interests: Die Manuskript-Erstellung wurde von Boehringer Ingelheim finanziell unterstützt. Keine(r) der Autor*innen hat für die Erstellung der Diagnose-Empfehlung eine finanzielle Gegenleistung erhalten. Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Due to the effects of climate change, winter sport enthusiasts will be increasingly forced to stay at higher altitudes. High altitude (HA) environmental factors such as cold temperature, physical exertion, and hypoxia with subsequent hypocapnia due to hyperventilation have been shown to induce bronchoconstriction. With bronchial asthma being highly prevalent, asthmatics also will be increasingly exposed to HA environment and might experience increasing symptoms., Methods: We analysed the effects of HA factors at around 2600 m a.s.l. (metres above sea level) on lung function in mild seasonal asthmatics while they were routinely off (January) and on (March, after start of lowland pollen season) low-dose inhaled corticosteroid (ICS) treatment (n = 10), and matched healthy controls (n = 11)., Results: Without inhaled corticosteroid (ICS) treatment mean FEV1 in asthmatics was 230 ml lower after exercise at HA compared to low altitude (LA, p < 0.05), while in healthy controls there was no significant difference. This decrease was mainly induced by cold and exercise at HA. During ICS treatment, this decrease was prevented. Methacholine response was reduced at HA compared to LA., Conclusions: The decrease of FEV1 in response to a combination of hypoxia, cold, and exercise is prevented by ICS treatment in mild, seasonal asthmatics. However, the FEV1 response to high altitude factors was overall small., (© 2022 The Author(s).)

Background: Everolimus-based quadruple low calcineurin inhibitor (CNI) maintenance immunosuppression has been shown to be effective in preserving short-term renal function without compromising efficacy or safety after lung transplantation; however, long-term benefit remains unknown., Methods: An investigator-initiated 5-y follow-up analysis of the 4EVERLUNG study (NCT01404325), comparing everolimus-based quadruple low CNI with standard triple regimen, was performed. Patients who remained on the randomized drug regimen until the end of the 5-y observation were analyzed as the per protocol (PP) population. Patients in whom the assigned regimen was switched were analyzed as the intention-to-treat (ITT) population., Results: In total, 123 patients (95%) from the core study were analyzed. During the observation period in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the assigned immunosuppressive regimen was switched ( P = 0.002). Estimated glomerular filtration rate at 5-y follow-up did not differ between the groups in both the ITT (56 [48-73] versus 58 [48-69] mL/min; P =0.951) and PP (59 [50-73] versus 59 [48-69] mL/min; P = 0.946) populations. Thromboembolic events occurred more frequently in the quadruple low CNI regimen (ITT: 11% versus 24%, P = 0.048; PP: 11% versus 22%, P = 0.162). There was a trend for a higher chronic lung allograft dysfunction-free survival for the quadruple low CNI regimen in the PP population ( P = 0.082). No difference in the graft survival was found., Conclusions: Initiation of an early everolimus-based quadruple low CNI regimen may have no long-term benefit on renal function. The immunosuppressive efficacy and safety profile seems comparable with the standard triple regimen., Competing Interests: N.K. reports personal fees from Novartis outside the submitted work. J.G. reports personal fees from Novartis during the conduct of the study and outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Liberation from prolonged tracheostomy ventilation involves ventilator weaning and removal of the tracheal cannula (referred to as decannulation). This study evaluated the incidence, causes, and predictors of unsuccessful decannulation following prolonged weaning., Methods: Observational retrospective cohort study of 532 prolonged mechanically ventilated, tracheotomized patients treated at a specialized weaning center between June 2013 and January 2021. We summarized the causes for unsuccessful decannulations and used a binary logistic regression analysis to derive and validate associated predictors., Results: Failure to decannulate occurred in 216 patients (41%). The main causes were severe intensive care unit (ICU)-acquired dysphagia (64%), long-term ventilator dependence following weaning failure (41%), excessive respiratory secretions (12%), unconsciousness (4%), and airway obstruction (3%). Predictors of unsuccessful decannulation from any cause were age [odds ratio (OR) = 1.04 year -1 ; 95% confidence interval (CI), 1.02-1.06; p  < 0.01], body mass index [0.96 kg/m 2 (0.93-1.00); p  = 0.027], Acute Physiology and Chronic Health Evaluation II (APACHE-II) score [1.05 (1.00-1.10); p  = 0.036], pre-existing non-invasive home ventilation [3.57 (1.51-8.45); p  < 0.01], percutaneous tracheostomies [0.49 (0.30-0.80); p  < 0.01], neuromuscular diseases [4.28 (1.21-15.1); p  = 0.024], and total mechanical ventilation duration [1.02 day -1 (1.01-1.02); p  < 0.01]. Regression models examined in subsets of patients with severe dysphagia and long-term ventilator dependence as the main reason for failure revealed little overlapping among predictors, which even showed opposite effects on the outcome. The application of non-invasive ventilation as a weaning technique contributed to successful decannulation in 96 of 221 (43%) long-term ventilator-dependent patients following weaning failure., Conclusion: Failure to decannulate after prolonged weaning occurred in 41%, mainly resulting from persistent ICU-acquired dysphagia and long-term ventilator dependence following weaning failure, each associated with its own set of predictors., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: COVID-19 causes a wide range of symptoms, with particularly high risk of severe respiratory failure and death in patients with predisposing risk factors such as advanced age or obesity. Recipients of solid organ transplants, and in particular lung transplantation, are more susceptible to viral infection owing to immune suppressive medication. As little is known about the SARS-CoV-2 infection in these patients, this study was undertaken to describe outcomes and potential management strategies in early COVID-19 infection early after lung transplantation., Methods: We describe the incidence and outcome of COVID-19 in a cohort of recent lung transplant recipients in Munich. Six of 186 patients who underwent lung transplantation in the period between March 2019 and March 2021 developed COVID-19 within the first year after transplantation. We documented the clinical course and laboratory changes for all patients showing differences in the severity of the infection with COVID-19 and their outcomes., Results: Three of 6 SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment after lung transplantation. All patients suffered from symptoms. One patient did not receive antiviral therapy. Remdesivir was prescribed in 4 patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma., Conclusions: COVID-19 does not appear to cause milder disease in lung transplant recipients compared with the general population. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss. Several comorbidities and a general poor preoperative condition showed an extended hospital stay., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx)., Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis., Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality ( p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk., Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions., Competing Interests: NK reports research funds and honoraria for consulting from Breath Therapeutics, a Zambon company, Italy. CN reports honoraria for consulting and advisory boards from Breath Therapeutics, a Zambon company, Italy and PARI GmbH, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kneidinger, Ghiani, Milger, Monforte, Knoop, Jaksch, Parmar, Ussetti, Solé, Müller-Quernheim, Voelp, Behr and Neurohr.)

SARS-CoV-2 has been the cause of a global pandemic since 2019 and remains a medical urgency. siRNA-based therapies are a promising strategy to fight viral infections. By targeting a specific region of the viral genome, siRNAs can efficiently downregulate viral replication and suppress viral infection. However, to achieve the desired therapeutic activity, siRNA requires a suitable delivery system. The VIPER (virus-inspired polymer for endosomal release) block copolymer has been reported as promising delivery system for both plasmid DNA and siRNA in the past years. It is composed of a hydrophilic block for condensation of nucleic acids as well as a hydrophobic, pH-sensitive block that, at acidic pH, exposes the membrane lytic peptide melittin, which enhances endosomal escape. In this study, we aimed at developing a formulation for pulmonary administration of siRNA to suppress SARS-CoV-2 replication in lung epithelial cells. After characterizing siRNA/VIPER polyplexes, the activity and safety profile were confirmed in a lung epithelial cell line. To further investigate the activity of the polyplexes in a more sophisticated cell culture system, an air-liquid interface (ALI) culture was established. siRNA/VIPER polyplexes reached the cell monolayer and penetrated through the mucus layer secreted by the cells. Additionally, the activity against wild-type SARS-CoV-2 in the ALI model was confirmed by qRT-PCR. To investigate translatability of our findings, the activity against SARS-CoV-2 was tested ex vivo in human lung explants. Here, siRNA/VIPER polyplexes efficiently inhibited SARS-CoV-2 replication. Finally, we verified the delivery of siRNA/VIPER polyplexes to lung epithelial cells in vivo, which represent the main cellular target of viral infection in the lung. In conclusion, siRNA/VIPER polyplexes efficiently delivered siRNA to lung epithelial cells and mediated robust downregulation of viral replication both in vitro and ex vivo without toxic or immunogenic side effects in vivo, demonstrating the potential of local siRNA delivery as a promising antiviral therapy in the lung., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 ( FKBP11 ) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.

Riociguat is licensed for the therapy of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to investigate whether age and comorbidities influence its tolerability and efficacy. Retrospectively, we analyzed data of tolerability, non-invasive, and invasive efficacy at baseline and follow up (FU) of all patients with CTEPH treated with riociguat at the Department of Internal Medicine V, University of Munich ( n = 47), grouping patients according to age (<65 versus 65-79 versus ≥80 years) and risk factors for heart failure with preserved ejection fraction (HFpEF) (<2 versus ≥2 risk factors). During dose titration patients >80 years reported side effects more frequently (40%) than the other age groups (23% and 21% for patients <65 years and patients 65-79, respectively). Cessation of riociguat was rare and occurred independent of age. When looking at the total cohort of 47 patients, three patients stopped therapy and three patients had a reduced maintenance dosage, while 41/47 (87%) and all octogenarians reached the highest maintenance dosage of 7.5 mg/d. The frequency of any side effect was similar in patients in both risk factor groups, and hypotension was only observed in those with <2 risk factors. Parameters of efficacy improved significantly under riociguat treatment. Improvement in 6-min walk distance (6 mwd), N-terminal pro brain natriuretic peptide (Nt-proBNP) and hemodynamics did not differ between age or risk factor groups. In this small real-life cohort, riociguat was well-tolerated and effective in advanced age and risk factors for HFpEF.

Objective: Evaluation of pulmonary function impairment after COVID-19 in persistently symptomatic and asymptomatic patients of all disease severities and characterisation of risk factors., Methods: Patients with confirmed SARS-CoV-2 infection underwent prospective follow-up with pulmonary function testing and blood gas analysis during steady-state cycle exercise 4 months after acute illness. Pulmonary function impairment (PFI) was defined as reduction below 80% predicted of DLCOcSB, TLC, FVC, or FEV1. Clinical data were analyzed to identify risk factors for impaired pulmonary function., Results: 76 patients were included, hereof 35 outpatients with mild disease and 41 patients hospitalized due to COVID-19. Sixteen patients had critical disease requiring mechanical ventilation, 25 patients had moderate-severe disease. After 4 months, 44 patients reported persisting respiratory symptoms. Significant PFI was prevalent in 40 patients (52.6%) occurring among all disease severities. The most common cause for PFI was reduced DLCOcSB (n = 39, 51.3%), followed by reduced TLC and FVC. The severity of PFI was significantly associated with mechanical ventilation (p < 0.001). Further risk factors for DLCO impairment were COPD (p < 0.001), SARS-CoV-2 antibody-Titer (p = 0.014) and in hospitalized patients CT score. A decrease of paO2 > 3 mmHg during cycle exercise occurred in 1/5 of patients after mild disease course., Conclusion: We characterized pulmonary function impairment in asymptomatic and persistently symptomatic patients of different severity groups of COVID-19 and identified further risk factors associated with persistently decreased pulmonary function. Remarkably, gas exchange abnormalities were revealed upon cycle exercise in some patients with mild disease courses and no preexisting pulmonary condition., (© 2021. The Author(s).)

A promising approach to tackle the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) could be small interfering (si)RNAs. So far it is unclear, which viral replication steps can be efficiently inhibited with siRNAs. Here, we report that siRNAs can target genomic RNA (gRNA) of SARS-CoV-2 after cell entry, and thereby terminate replication before start of transcription and prevent virus-induced cell death. Coronaviruses replicate via negative sense RNA intermediates using a unique discontinuous transcription process. As a result, each viral RNA contains identical sequences at the 5' and 3' end. Surprisingly, siRNAs were not active against intermediate negative sense transcripts. Targeting common sequences shared by all viral transcripts allowed simultaneous suppression of gRNA and subgenomic (sg)RNAs by a single siRNA. The most effective suppression of viral replication and spread, however, was achieved by siRNAs that targeted open reading frame 1 (ORF1) which only exists in gRNA. In contrast, siRNAs that targeted the common regions of transcripts were outcompeted by the highly abundant sgRNAs leading to an impaired antiviral efficacy. Verifying the translational relevance of these findings, we show that a chemically modified siRNA that targets a highly conserved region of ORF1, inhibited SARS-CoV-2 replication ex vivo in explants of the human lung. Our work encourages the development of siRNA-based therapies for COVID-19 and suggests that early therapy start, or prophylactic application, together with specifically targeting gRNA, might be key for high antiviral efficacy., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Since critical respiratory muscle workload is a significant determinant of weaning failure, applied mechanical power (MP) during artificial ventilation may serve for readiness testing before proceeding on a spontaneous breathing trial (SBT). Secondary analysis of a prospective, observational study in 130 prolonged ventilated, tracheotomized patients. Calculated MP's predictive SBT outcome performance was determined using the area under receiver operating characteristic curve (AUROC), measures derived from k-fold cross-validation (likelihood ratios, Matthew's correlation coefficient [MCC]), and a multivariable binary logistic regression model. Thirty (23.1%) patients failed the SBT, with absolute MP presenting poor discriminatory ability (MCC 0.26; AUROC 0.68, 95%CI [0.59‒0.75], p = 0.002), considerably improved when normalized to lung-thorax compliance (LTC dyn -MP, MCC 0.37; AUROC 0.76, 95%CI [0.68‒0.83], p < 0.001) and mechanical ventilation P a CO 2 (so-called power index of the respiratory system [PI rs ]: MCC 0.42; AUROC 0.81 [0.73‒0.87], p < 0.001). In the logistic regression analysis, PI rs (OR 1.48 per 1000 cmH 2 O 2 /min, 95%CI [1.24‒1.76], p < 0.001) and its components LTC dyn -MP (1.25 per 1000 cmH 2 O 2 /min, [1.06‒1.46], p < 0.001) and mechanical ventilation P a CO 2 (1.17 [1.06‒1.28], p < 0.001) were independently related to SBT failure. MP normalized to respiratory system compliance may help identify prolonged mechanically ventilated patients ready for spontaneous breathing., (© 2022. The Author(s).)