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Introduction: The Seraph 100 Microbind Affinity blood filter eliminate bacteria, viruses, fungi and toxins from blood stream., Methods: This is a prospective multicenter observational biomarker trial in PCR-positive SARS-CoV-2 patients with acute respiratory failure. Biomarkers were sequentially tested at three time points., Results: Forty-two patients with SARS-CoV-2 detected by PCR with acute respiratory failure were included. When receiving hemoperfusion treatment, 27 (64%) patients were on mechanical ventilation, 41 (98%) patients were treated in the ICU. The 3-month survival was 52%. After one hemoperfusion treatment cycle, D-dimer (p = 0.014), hemoglobin (p = 0.003) and LDH (p = 0.001) concentrations were significantly reduced 4 days after treatment. From the multiplex assay IL-1b, CXCL8/ IL-8, IL-10, IL-13, IL-15, CCL11/Eotaxin, G-CSF, and CXCL10/IP-10 were significantly reduced 1 h after treatment, however not 4 days later., Conclusion: Hemoperfusion with Seraph 100 Microbind Affinity Filter in patients with severe COVID-19 can transiently reduce several inflammatory biomarkers in the blood., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Background: Many hospitalized patients decline in functional status after discharge, but functional decline in emergency admissions with hypoxemia is unknown. The primary aim of this study was to study functional outcomes as a clinical endpoint in a cohort of patients with acute hypoxemia., Methods: A multicenter prospective observational study was conducted in patients with new-onset hypoxemia emergently admitted to two respiratory departments at a university hospital and an academic teaching hospital. Using the WHO scale, the patients' functional status 4 weeks before admission and at hospital discharge was assessed. The type and duration of oxygen therapy, hospital length of stay and survival and risk of hypercapnic failure were recorded., Results: A total of 151 patients with a median age of 74 were included. Two-thirds declined in functional status by at least one grade at discharge. A good functional status (OR 4.849 (95% CI 2.209-10.647)) and progressive cancer (OR 6.079 (1.197-30.881)) were more associated with functional decline. Most patients were treated with conventional oxygen therapy (n = 95, 62%). The rates of in-hospital mortality and need for intubation were both 8%., Conclusions: Patients with acute hypoxemia in the emergency room have a poorer functional status after hospital discharge. This decline may be of multifactorial origin., Competing Interests: Jens Gottlieb reports institutional research grants from Zambon/Breath Therapeutics, German Center of Lung Research, Deutsche Forschungsgemeinschaft. He also received fees for advisory/consultancy from Theravance, Pierre Fabre, Atheneum, Merck, Springer Healthcare and the European Research Network, and speaker fees from Novartis, Astra Zeneca and CSL Behring. He owns stock options from Pfizer. He serves as a member of the ScanCLAD study’s data safety monitoring board. All disclosures are unrelated to the current work. Susanne Simon, Ina Burchart and René Abu Isneineh report no disclosures. Thomas Fuehner reports speaker fees from Novartis and Astra Zeneca. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Chronic lung allograft dysfunction (CLAD) is a leading cause of graft loss in lung transplantation. Despite this, convincing treatment data is lacking, and protocols vary widely between centers. CLAD phenotypes exist, but phenotype transitioning has increased the challenge of designing clinically relevant studies. Extracorporeal photopheresis (ECP) has long been a suggested salvage treatment, but efficacy appears unpredictable. This study describes our experiences with photopheresis, using novel temporal phenotyping to illustrate the clinical course., Methods: Retrospective analysis of patients completing ≥3 months of ECP for CLAD between 2007 and 2022 was performed. A latent class analysis employing a mixed-effects model was performed, deriving patient subgroups based on spirometry trajectory over the 12 months prior to photopheresis until graft loss or 4 years post photopheresis initiation. The resulting temporal phenotypes were compared in terms of treatment response and survival outcomes. Linear discriminatory analysis was used to assess phenotype predictability, relying solely on data available at photopheresis initiation., Results: Data from 5,169 outpatient attendances in 373 patients was used to construct the model. Five trajectories were identified, with uniform spirometry changes evident following 6 months of photopheresis. Outcomes were poorest in Fulminant patients (N = 25, 7%) with median survival of 1 year. In the remainder, poorer lung function at initiation led to poorer outcomes. The analysis revealed important confounders, affecting both decision-making and outcome interpretation., Conclusions: Temporal phenotyping provided novel insights into ECP treatment response in CLAD, particularly the importance of timely intervention. Limitations in % Baseline values in guiding treatment decisions warrant further analysis. Photopheresis may have a more uniform effect than previously thought. Predicting survival at ECP initiation appears feasible., Competing Interests: Disclosure statement MG has previously received speaker fees from Therakos. Neither Therakos nor any of their partners were involved or indeed had any prior knowledge of the manuscript at any stage prior to publication. JMM reports institutional grants and speaker fees from Boehringer Ingelheim. FI reports consulting and speaker fees as well as travel support grants from Biotest AG. TW has received research grants from the German Ministry for Research and Education for projects unrelated to this manuscript. None of the other authors reported any relevant financial interests., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Obstructive airway complications (OACs) represent a significant problem after lung transplantation (LTx). Bilateral OACs after double lung transplantation are infrequently reported., Objectives: The aim of this study was to investigate management and outcome of OAC., Design: Retrospective single-center cohort study., Methods: Adult patients with bilateral LTx performed between 2010 and 2021 were included. Patients with follow-ups of less than 3 months and after heart-lung transplantation were excluded. OAC was defined either as the need for stenting, surgical revision, or balloon dilatation. Outcome parameters included graft survival, graft function, quality of life, and management., Results: During the study period, 1,170 patients were included. Hundred thirty-five (11.5%) patients developed OAC. Forty-six (4.4%) patients had significant bilateral OAC. Thirty-seven (80%) bilateral OAC patients were treated by stent insertion; in 34 patients, biodegradable stents were used. The median number of bronchoscopies in bilateral OAC was 26 during the first postoperative year compared with nine in controls ( p  < 0.001). Fourteen OAC patients ( n  = 10 bilateral) underwent surgical revision including six re-do transplantations. Graft loss occurred significantly more frequently in patients with bilateral OAC with a graft survival of 63% and 50% in these after 3 and 5 years compared with 83% and 73% in controls without OAC ( p  < 0.001). Baseline forced expiratory volume in 1 s (FEV1) in patients with bilateral OAC was median 58% predicted in comparison with 90% in controls ( p  < 0.001). Quality of life was significantly reduced., Conclusion: Bilateral OACs impose a high burden of disease on patients after lung transplantation and were associated with early and late graft loss. Affected patients' OAC demonstrated reduced graft function and impaired quality of life. Most OACs were managed by bronchoscopy preferably by non-permanent stenting. Surgery including re-do transplantation was used in selected cases.

Background: The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global crisis challenging the worldwide healthcare systems. Many patients present with a mismatch of profound hypoxemia and few signs of respiratory distress (i.e., silent hypoxemia). This particular clinical presentation is often cited, but data are limited., Main Body: We describe dyspnea sensation as assessed by using the BORG scale in pulmonary patients admitted to the emergency room during a 4-week period and transferred to the respiratory department of Siloah Hospital, Hannover, Germany. From October 1 to November 1, 2020, 82 patients with hypoxemia defined as oxygen demand to achieve an oxygen saturation (SpO2) ≥92% were included. In 45/82 (55%) patients, SARS-CoV-2 was detected by PCR on admission. Among non-COVID patients, exacerbation of COPD was the main diagnosis (15/37, 41%). All subjects rated their perceived dyspnea using the modified Borg CR10 scale. Patients in the non-COVID group suffered from more dyspnea on the modified Borg CR10 scale (median 1, IQR: 0-2 vs. median 5, IQR: 3-6, p < 0.001). In multivariate analysis, "silent hypoxemia" as defined by the dyspnea Borg CR10 scale ≥5 was independently associated with COVID-19 and presence of severe hypocapnia with an odds ratio of 0.221 (95% confidence interval 0.054, 0.907, p 0.036)., Conclusion: Among pulmonary patients with acute hypoxemia defined as oxygen demand, patients suffering from COVID-19 experience less dyspnea compared to non-COVID patients. "Silent" hypoxemia was more common in COVID-19 patients., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.

Background: Bronchoscopy is widely used and regarded as standard of care in most intensive care units (ICUs). Data concerning recommendations for on-call bronchoscopy are lacking., Objectives: Evaluation of recommendations, complications, and outcome of on-call bronchoscopies., Method: A retrospective single-centre analysis was conducted in a large university hospital. All on-call bronchoscopies performed outside normal working hours in the year before (period 1) and after (period 2) establishing a catalogue of recommendations for indications of on-call bronchoscopy on November 1, 2016, were included., Results: Overall, 924 bronchoscopies in 538 patients were analysed. A relative reduction of 83.6% from 794 bronchoscopies in 432 patients (1.84 per patient) during period 1 to 130 in 107 patients (1.21 per patient) during period 2 was observed. Most bronchoscopies (812/924, 87.9%) were performed in ICUs, and 416 patients (77.3%) were intubated. Bronchoscopies for excessive secretions decreased significantly during period 2. Fifty-three of 130 bronchoscopies (40.8%) fulfilled the specified recommendations during period 2, in comparison with 16.8% in period 1 (p < 0.001). Complications were recorded in 58 of 924 procedures (6.3%) and were more frequent in period 2, especially moderate bleeding. In-hospital mortality of patients undergoing on-call bronchoscopy did not differ between periods and was 28.7 and 30.2% in periods 1 and 2, respectively., Conclusion: The introduction of recommendations for on-call bronchoscopy led to a significant decline of on-call bronchoscopies without negatively affecting outcome. More evidence is needed in on-call bronchoscopy, especially for ICU patients with intrinsic higher complication rates., (© 2021 S. Karger AG, Basel.)

Background: The use of e-cigarettes is on the rise around the world. Many case reports of acute lung injury due to e-cigarette use have been published in recent months in the USA, but no comparable cases have emerged in Germany up to the present report. The use of e-cigarettes has risen very rapidly in the USA in recent years, simultaneously with the legalization of marijuana sale in many American states. Most of the cases described there involved the use, not only of nicotine, but of tetrahydrocannabinol (THC, the psychoactive ingredient in marijuana) as well, though some of the patients had indeed not used additives (e.g. THC)., Methods: We report three cases in Germany of acute pulmonary illness that we consider to have been caused by the use of e-cigarettes., Results: All three patients were hospitalized for acute shortness of breath. Two displayed partial respiratory insufficiency and bilateral pulmonary infiltrates. All three stated that they had used ordinary, commercially available e-cigarettes every day for at least the past three months. In the first patient, a 48-year-old man, the complete blood count and bronchial lavage findings indicated eosinophilic inflammation. The second patient, a 22-year-old man, developed multiple episodes of hemoptysis, with computed tomography (CT) showing diffuse alveolar bleeding; his complete blood count also revealed eosinophilic inflammation. The third patient, a 34-year-old man, displayed acute ground-glass lung opacities as well as fibrosing changes on CT corresponding to pulmonary sarcoidosis. All three recovered on high-dose systemic corticosteroid treatment and were discharged from the hospital in 2 to 12 days., Conclusion: In the first two cases, acute pulmonary injury was very likely due to e-cigarette consumption, as all other possible causes were ruled out. A possible link to e-cigarette use was present in the third case. We thus describe the first three suspected cases of acute lung disease due to e-cigarette use in Germany. These patients do not share any common, typical clinical picture; rather, their symptoms represent different components of the wide spectrum of interstitial lung disease. A uniform national registry should be established to improve our understanding of the adverse effects of e-cigarettes and the resulting acute and chronic changes in the lungs.

Background: Targeted therapies are the standard treatment in patients with metastatic renal cell carcinoma (mRCC) and are known to cause adverse pulmonary events. Organizing pneumonia (OP) with its various manifestations in computed tomography (CT) has therefore lately received more attention., Purpose: To describe the spectrum of CT patterns of OP in patients with mRCC receiving targeted therapies., Material and Methods: Seventeen patients with known therapy-related OP were analyzed retrospectively by two blinded radiologists in consensus. Images were scored according to OP patterns that have previously been described. Additionally, the distribution and the predominant imaging pattern in each patient were determined., Results: In our cohort, ground glass opacity was the most common imaging pattern (17/17, 100%) in patients with OP followed by a reticular pattern (12/17, 71%), consolidations (10/17, 59%), nodules (7/17, 41%), crazy paving (5/17, 29%), bronchi(ol)ectasis (4/17, 24%), focal mass (3/17, 18%), and reversed halo (1/17, 6%). The most common imaging pattern was changing multifocal consolidations (8/17, 47%). A bronchocentric and a nodular pattern were found in four patients (24%) each, a progressive fibrotic pattern in none patient, and reversed halo/atoll pattern in one (6%) case., Conclusion: OP is the major differential diagnosis to be considered in patients with targeted therapies and pulmonary changes. Knowledge of the variety of imaging findings can facilitate diagnosis.

Among various innate immune receptor families, the role of C-type lectin receptors (CLRs) in lung protective immunity against Streptococcus pneumoniae (S. pneumoniae) is not fully defined. We here show that Mincle gene expression was induced in alveolar macrophages and neutrophils in bronchoalveolar lavage fluids of mice and patients with pneumococcal pneumonia. Moreover, S. pneumoniae directly triggered Mincle reporter cell activation in vitro via its glycolipid glucosyl-diacylglycerol (Glc-DAG), which was identified as the ligand recognized by Mincle. Purified Glc-DAG triggered Mincle reporter cell activation and stimulated inflammatory cytokine release by human alveolar macrophages and alveolar macrophages from WT but not Mincle KO mice. Mincle deficiency led to increased bacterial loads and decreased survival together with strongly dysregulated cytokine responses in mice challenged with focal pneumonia inducing S. pneumoniae, all of which was normalized in Mincle KO mice reconstituted with a WT hematopoietic system. In conclusion, the Mincle-Glc-DAG axis is a hitherto unrecognized element of lung protective immunity against focal pneumonia induced by S. pneumoniae., Competing Interests: The authors have declared that no competing interests exist.

Lung transplantation (LTx) has become an accepted treatment for carefully selected patients with end-stage lung disease. Critical care issues have gained importance concerning bridging of candidates by mechanical respiratory support and are involved in the care after transplantation. The nature of respiratory support varies from oxygen supply and noninvasive ventilation, to mechanical respiratory support either by mechanical ventilation and/or extracorporeal life support. Recent innovations in extracorporeal life support technology have resulted in its more widespread use. Retrospective studies have demonstrated promising outcomes in candidates on mechanical respiratory support as a bridge to lung transplantation. The role of mechanical respiratory support has influenced the selection criteria for LTx, although bridging remains technically and ethically challenging. Critical care is integral to manage and prevent postoperative complications of LTx. Primary graft dysfunction and prolonged mechanical ventilation are major obstacles to hospital survival after LTx. Clear evidence is lacking on how to ventilate and optimally manage patients after LTx. Prolonged extracorporeal life support after LTx may improve outcome in selected patients with a primary graft dysfunction., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Topical airway anesthesia is known to improve tolerance and patient satisfaction during flexible bronchoscopy (FB). Lidocaine is commonly used, delivered as an atomized spray. The current study assesses safety and patient satisfaction for nasal anesthesia of a new atomization device during outpatient bronchoscopy in lung transplant recipients., Methods: Using a prospective, non-blinded, cross-over design, patients enrolled between 01-10-2014 and 24-11-2014 received 2% lidocaine using the standard reusable nasal atomizer (CRNA). Those enrolled between 25-11-2014 and 30-01-2015, received a disposable intranasal mucosal atomization device (DIMAD). After each procedure, the treating physician, their assistant and the patient independently rated side-effects and satisfaction, basing their responses on visual analogue scales (VAS). At their next scheduled bronchoscopy during the study period, patients then received the alternative atomizer. Written consent was obtained prior to the first bronchoscopy, and the study approved by the institutional ethics committee., Results: Of the 252 patients enrolled between 01-10-2014 and 30-01-2015, 80 (32%) received both atomizers. Physicians reported better efficacy (p = 0.001) and fewer side effects (p< = 0.001) for DIMAD in patients exposed to both procedures. Among patients with one visit, physicians and their assistants reported improved efficacy (p = 0.018, p = 0.002) and fewer side effects (p< = 0.001, p = 0.029) for the disposable atomizer, whereas patients reported no difference in efficacy or side effects (p = 0.72 and p = 0.20). No severe adverse events were noted. The cost of the reusable device was 4.08€ per procedure, compared to 3.70€ for the disposable device., Discussion: Topical nasal anesthesia via a disposable intranasal mucosal atomization device (DIMAD) offers comparable safety and patient comfort, compared to conventional reusable nasal atomizers (CRNA) in lung transplant recipients. Procedural costs were reduced by 0.34€ per procedure., Trial Registration: clinicaltrials.gov NCT02237651.

Background: Chronic lung allograft dysfunction (CLAD) is the major outcome limitation for lung transplant recipients (LTR) after the first year, and therapies targeting immunological pathways show only limited success. Because microvesicles (MV) are biomarkers of endothelial dysfunction and coagulation but are also involved in immunological responses, we hypothesized that MV, found in bronchoalveolar lavage (BAL) fluids (BALF) of LTR at CLAD diagnosis, are elevated and potential prognostic biomarkers., Methods: The BALF was collected from 37 LTR at time point of CLAD diagnosis and 37 LTR without any complication at routinely performed BAL. The MV concentration and origin were determined by flow cytometry by detection of different antigens. Patient- and transplant-related risk factors were included in a retrospective statistical analysis., Results: The BALF-MV levels of epithelial and red blood cell (RBC) origin were significantly higher in CLAD patients (mean: 1533/μL and 158/μL) compared to controls (436/μL, 57/μL). The LTR with high levels of epithelial MV >580/μL showed a significantly shorter overall survival at 4 years after BAL (39.5%) compared to patients with low MV (66.4%) and this proofed to be an independent prognostic factor in multivariate Cox analysis (hazards ratio = 3.05). Furthermore, LTR with high levels of RBC MV ≥225/μL were also associated with worse disease-specific survival, with probabilities at 4 years after BAL of 85.8% vs. 36.0%., Conclusions: Epithelial and RBC BALF-MV are elevated at CLAD diagnosis, have a potential as biomarkers, and support the hypothesis of a pathway, including activation of coagulation and complement, endothelial barrier dysfunction, and microangiopathy.

Background: Mediocre donation rates and increasing demand for lung transplantation leads transplant centers to consider extended-criteria donor lungs. Arguably, the largest remaining non-utilized lung donor segment is the elderly individual, already considered for visceral organ donation but not thoracic. So far, transplantation of donor lungs aged ≥ 70 years is rarely reported, and recipient outcomes are unknown. Accordingly, we report a single-center series of lung transplantations from donors aged ≥ 70 years and compare outcomes with contemporary lung transplantations from younger donors., Methods: All bilateral lung transplantations performed at our center between March 2011 and July 2014 were analyzed, and 2 cohorts were built according to lung donor age., Results: A total of 440 bilateral lung transplantations were performed from 413 donors aged <70 years, and 27 donors aged ≥70 years. Donor characteristics did not differ in sex, donor time on mechanical ventilation before retrieval, or donor partial pressure of arterial oxygen/fraction of inspired oxygen ratio. Older donors were significantly less often positive for smoking history (43.7% vs 14.8%, p = 0.003) or for abnormal bronchoscopy results (52.9% vs 15.8%, p = 0.002). Recipients receiving donor lungs aged <70 years were younger than those receiving older donor lungs ≥ 70 (49.8 [range, 35-58] vs 58 [range, 53-62] years, p < 0.0001). Underlying diagnoses did not differ significantly between the groups. Post-operative mechanical ventilation times (15 [range, 10-59] vs 27.5 [range, 10-75.8] hours), intensive care unit stays (3 [range, 1-5] vs 3 [range, 1-8] days), and total hospital lengths of stay (24 [range, 22-40.5] vs 24 [range, 22-40] days) of the recipients did not differ significantly between the two groups. The percentage predicted forced expiratory volume in 1 second was 86.5% ± 26.2% 12 months after transplantation of younger lungs vs 72.2% ± 23.8% (p = 0.01) after transplantation of older lungs. Differentiating the spirometry findings according to underlying diseases showed significantly lower forced expiratory volume in 1 second values after transplantation of donor lungs aged ≥70 only in idiopathic pulmonary fibrosis recipients but not in emphysema patients. Patient survival up to 36 months was not significantly different, with 1-year survival being 92.9% for younger vs 95.5% for older donor lungs., Conclusion: Use of donor lungs aged ≥70 years for transplantation is safe, without compromising survival. However, spirometry findings after transplantation with donors ≥70 years indicate better functional outcomes in emphysema recipients than in idiopathic pulmonary fibrosis recipients., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Lung transplant recipients (LTRs) are at life-long risk for infections and disseminated diseases owing to their immunocompromised state. Besides organ failure and sepsis, infection can trigger acute and chronic graft rejection which increases mortality. Medical prophylaxis and treatment are based on comprehensive diagnostic work-up including previous history of infection and airway colonisation to reduce long-term complications and mortality. Common bacterial pathogens include Pseudomonas and Staphylococcus, whilst Aspergillus and Cytomegalovirus (CMV) are respectively the commonest fungal and viral pathogens. Clinical symptoms can be various in lung transplant recipients presenting an asymptomatic to severe progress. Regular control of infection parameters, daily lung function testing and lifelong follow-up in a specialist transplant centre are mandatory for early detection of bacterial, viral and fungal infections. After transplantation each patient receives intensive training with rules of conduct concerning preventive behaviour and to recognize early signs of post transplant complications. Early detection of infection and complications are important goals to reduce major complications after lung transplantation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Endoscopic lung volume reduction (ELVR) has become an established treatment option in selected patients with end-stage lung emphysema. ELVR, however, does not always prevent disease progression, and patients may inevitably be considered for lung transplantation., Objectives: Currently, limited data exist regarding the impact of preceding ELVR on lung transplantation outcomes., Methods: A retrospective, single-center analysis of lung transplantation (LTx) waiting list candidates, who had previously undergone ELVR for emphysema between 2010 and 2014, was performed. Outcomes were compared to matched (1:2) controls who underwent LTx for emphysema without previous ELVR. The 12-month survival after LTx represented the primary end point., Results: In total 23/693 (3%) patients listed for LTx between January 2010 and May 2014 had undergone ELVR, of whom 20/23 (87%) proceeded to LTx (ELVR group). Forty matched non-ELVR emphysema patients acted as controls. Bronchiectasis on CT prior to LTx was more evident in ELVR patients [11/20 (55%) vs. 12/40 (30%); p = 0.04] as well as airway colonization after LTx [10/20 (50%) vs. 6/40 (15%); p = 0.004]. Among ELVR patients, the most prevalent colonizing organism was Stenotrophomonas maltophilia (4/10 patients, 40%). No significant differences were observed in LTx waiting list time, duration of LTx procedure, ventilatory support, ICU stay after LTx or time to hospital discharge. One ELVR patient (5%) died 189 days after LTx from pneumonia, compared to 1 non-ELVR patient (3%) who died after 269 days (p = 0.61)., Conclusions: Previous ELVR treatment was not associated with differing outcomes following LTx. Increased bacterial colonization rates were evident and warrant further investigation., (© 2015 S. Karger AG, Basel.)

Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.

Background: Several case series and small randomized controlled trials suggest that therapeutic plasma exchange (TPE) improves coagulation, hemodynamics and possibly survival in severe sepsis. However, the exact role of TPE in modern sepsis therapy remains unclear., Methods: We performed a retrospective observational single-centre study on the use of TPE as rescue therapy in 23 consecutive patients with severe sepsis or septic shock from 2005 to 2012. Main surrogate markers of multiple organ failure (MOF) before, during and after TPE as well as survival rates are reported., Results: At baseline, mean SOFA score was 13 (standard deviation [SD] 4) and median number of failed organ-systems was 5 (interquartile range [IQR] 4-5). TPEs were performed 3 days (IQR 2-10) after symptom onset and 1 day (IQR 0-8) after ICU admission. The median total exchange volume was 3750 ml (IQR 2500-6000), which corresponded to a mean of 1.5 times (SD 0.9) the individual plasma volume. Fresh frozen plasma was used in all but one treatments as replacement fluid. Net fluid balance decreased significantly within 12 hrs following the first TPE procedure by a median of 720 mL (p = 0.002), irrespective of outcome. Reductions of norepinephrine dose and improvement in cardiac index were observed in individual survivors, but this was not significant for the overall cohort (p = 0.574). Platelet counts decreased irrespective of outcome between days 0 and 2 (p < 0.003), and increased thereafter in many survivors. There was a non-significant trend towards younger age and higher procalcitonin levels among survivors. Nine out of 23 TPE treated patients (39%) survived until ICU discharge (among them 3 patients with baseline SOFA scores of 15, 17, and 20)., Conclusions: Our data suggest that some patients with severe sepsis and septic shock may experience hemodynamic stabilisation by early TPE therapy.

Background: The antihypertensives reserpine and verapamil are also inhibitors of pneumococcal efflux pumps. We addressed the following questions: (i) Do verapamil and reserpine influence the mutation ratio of pneumococci in the presence of ciprofloxacin? (ii) At which concentrations does this occur? (iii) Is this limited to isolates with efflux phenotype?, Methods: 14 clinical isolates, nested in 6 genetically similar clusters, were used, 7 strains with efflux and 7 without. The mutation ratio in the presence of ciprofloxacin (3 × MIC) and increasing concentrations of reserpine and verapamil was determined and the quinolone-resistance determining regions (QRDR) of selected mutants were sequenced. Analysis of the efficacy was performed using a mixed linear model, supported by descriptive statistics., Results: Reserpine and verapamil reduced the mutation ratio of QRDR in the presence of ciprofloxacin with the required concentration for a reduction ≥ 50% of 1mg/l for reserpine and 50mg/l for verapamil. The mutation prevention effect is not limited to, but is more pronounced in efflux positive phenotypes., Conclusion: Reserpine and verapamil can prevent the selection of ciprofloxacin resistant isolates by reduction of the mutation ratio, particularly in strain with an efflux phenotype. However, the required concentrations are too toxic for clinical use., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Pulmonary rehabilitation (PR) is a cornerstone of treatment following lung transplantation (LTx). The aim of this study was to observe the influence of a prolonged postsurgical clinical course on success of a 3-week inpatient PR. LTx recipients were divided according to their clinical course defined by their individual length of stay (LOS) in the transplant center (cohort 1: LOS >; cohort 2: ≤42 days). Peak work rate (PWR), maximum oxygen uptake (VO(2max) ), 6-min walk distance (6-MWD), vital capacity (VC), forced expiratory volume in one second (FEV1), physical activity of daily life (ADL), and health-related quality of life (HRQoL) measured using Short Form 36 questionnaire (SF36) were assessed at beginning and completion of PR. A total of 138 patients were included (LOS >42 days: 30; LOS ≤42 days: 108). At completion, physical functioning (VC, FEV1, PWR, VO(2max) , 6-MWD, ADL), and HRQoL (all SF36 domains) improved in each cohort (P < 0.05). No differences were found in between both cohorts in VC, FEV1, and ADL (n.s.), but in PWR, 6-MWD, and the SF36 domain 'physical functioning' (P < 0.05). A 3-week inpatient PR improves physical functioning despite prolonged hospitalization. HRQoL is close to normal. (ClinicalTrials.gov. identifier: NCT00759538)., (© 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.)

Objectives: Patients requiring extracorporeal cardiorespiratory support during lung transplantation can be treated with conventional cardiopulmonary bypass (CPB) or venoarterial extracorporeal membrane oxygenation (ECMO). In a retrospective analysis, we compared the postoperative course and outcomes of patients treated using these approaches., Methods: Between August 2008 and September 2011, 92 consecutive patients underwent lung transplantation with extracorporeal support (CPB group, n = 46; and, since February 2010, ECMO group, n = 46) at our institution. We evaluated survival, secondary organ failure, bleeding complications, and the need for blood and platelet transfusions in these 2 patient populations., Results: Intraoperatively, the CPB group required more packed red blood cell transfusions (12 ± 11 vs 7 ± 9 U; P = .01) and platelet concentrates (2.5 ± 1.6 vs 1.5 ± 1 U; P < .01) than the ECMO group. In-hospital mortality (39% vs 13%; P = .004), the need for hemodialysis (48% vs 13%; P < .01), and new postoperative ECMO support (26% vs 4%; P < .01) were greater in the CPB group than in the ECMO group, respectively. After propensity score analysis, multivariate analysis identified retransplantation (odds ratio, 7; 95% confidence interval, 1-43; P = .034) and transplantation with CPB support (odds ratio, 4.9; 95% confidence interval, 1.2-20; P = .026) as independent risk factors for in-hospital mortality. The survival rate at 3, 9, and 12 months was 70%, 59%, and 56% in the CPB group and 87%, 81%, and 81% in the ECMO group (P = .004)., Conclusions: Intraoperative ECMO allows for better periprocedural management and reduced postoperative complications and confers a survival benefit compared with CPB, mainly because of lower in-hospital mortality. It is now the standard of care in our lung transplantation program., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Purpose of Review: Lung transplantation (LTx) has become established as a standard intervention for patients suffering from end-stage lung disease. Transplant recipients are, however, predisposed to numerous unique complications arising from the surgery, transplant immunology and the lifelong medication. Clinicians working in intensive care are increasingly likely to be exposed to these patients and it is therefore important to have a working knowledge of the common complications., Recent Findings: Common complications encountered following LTx include primary graft dysfunction (PGD), airway complications, acute rejection, chronic lung allograft dysfunction (CLAD), thrombotic microangiopathy (TMA) and infection, all of which impact significantly on long-term survival. PGD arises in the first weeks following transplantation. Acute rejection, airway complications and TMA represent the main complications in the first posttransplantation year. CLAD usually occurs later, but continues to represent the main obstacle to long-term survival. Infection poses significant risk at all stages following transplantation and a full spectrum of bacterial, fungal and viral pathogens has been implicated., Summary: This review highlights the most important complications after LTx and gives an update on diagnostic algorithms and treatment challenges for patients following LTx.

Rationale: The use of extracorporeal membrane oxygenation (ECMO) in patients who are awake and spontaneously breathing may represent a novel bridging strategy toward lung transplantation (LuTx)., Objectives: To evaluate the outcomes of patients treated with the "awake ECMO" concept as bridge to transplantation., Methods: We performed a retrospective, single-center, intention-to-treat analysis of consecutive LuTx candidates with terminal respiratory or cardiopulmonary failure receiving awake ECMO support. The outcomes were compared with a historical control group of patients treated with conventional mechanical ventilation (MV group) as bridge to transplant., Measurements and Main Results: Twenty-six patients (58% female; median age, 44 yr; range, 23-62) were included in the awake ECMO group and 34 patients (59% female; median age, 36 yr; range, 18-59) in the MV group. The duration of ECMO support or MV, respectively, was comparable in both groups (awake ECMO: median, 9 d; range, 1-45. MV: median, 15 d; range, 1-71; P = 0.25). Six (23%) of 26 patients in the awake ECMO group and 10 (29%) of 34 patients in the MV group died before a donor organ was available (P = 0.20). Survival at 6 months after LuTx was 80% in the awake ECMO group versus 50% in the MV group (P = 0.02). Patients in the awake ECMO group required shorter postoperative MV (P = 0.04) and showed a trend toward a shorter postoperative hospital stay (P = 0.06)., Conclusions: ECMO support in patients who are awake and nonintubated represents a promising bridging strategy, which should be further evaluated to determine its role in patients with end-stage lung disease awaiting LuTx.

Background: Paramyxovirus (PV) infections are increasingly recognized in lung transplant recipients and have been linked to subsequent graft failure and bronchiolitis obliterans syndrome (BOS). Ribavirin represents a possible treatment option although the outcome on graft function and BOS incidence is unknown., Methods: We analysed outcomes of all PV infections in lung/heart-lung recipients between September 2006 and April 2009 in a single centre. PV-infected recipients treated with oral ribavirin were compared with those unable to receive ribavirin due to contraindications. Recovery of graft function, time to recovery and new development of BOS were compared., Results: A total of 38 patients (ribavirin group) were treated with ribavirin for a median of 9 days (IQR 8-12), whilst 29 patients (non-ribavirin group) received best supportive care including corticosteroids. The median forced expiratory volume in 1 s dropped 20% (IQR 15-32) from baseline in the ribavirin group versus 18% (IQR 13-30) in the non-ribavirin group during infection. In 84% of patients treated with ribavirin and 59% of the non-ribavirin group, graft function recovered within 30 days (P=0.02). New onset of BOS developed within 6 months in 5% of the ribavirin group versus 24% of the non-ribavirin group (P=0.02)., Conclusions: Treatment of PV after lung/heart-lung transplantation with oral ribavirin seems to be associated with earlier recovery of graft function and to prevent BOS.

Background: Obstructive airway complications (OACs) are a significant cause of morbidity after lung transplantation (LTx). Endoscopic evaluation early after LTx may help earlier identification of patients at risk., Methods: Anastomotic healing process was prospectively evaluated in 169 LTx recipients by bronchoscopy between 2007 and 2009 in a single center. Bronchoscopies were performed on day 7, 14, 21, 90, 180, and 360 after LTx. A scoring system of airway healing was constructed., Results: In 42 of 169 patients (25%), OAC occurred. Dehiscence (P≤0.001), extensive necrosis (P=0.001), fibrinous plug (P≤0.001), and mucosal healing at segmental level (P=0.001) on day 21 after LTx were significantly associated with later occurrence of OAC. The hereby developed Mucosal Airway Score for Healing (0-8 points, cutoff >3 points) proved to predict later OAC in 67 patients of validation phase (sensitivity=0.97; specificity=0.93; positive predictive value=0.85; and negative predictive value=0.96). Substantial interobserver agreement using Mucosal Airway Score for Healing was achieved (κ=0.617). All airway complications were managed with endoscopic intervention, and no surgical treatment was necessary., Conclusion: Endoscopic appearance on day 21 after LTx predicts later occurrence of OAC. The resulting scoring system may be used in the early postoperative period as a tool to assess preventive strategies.

Context: Complications often occur during the early phase after lung transplantation, and rapid diagnosis is vital. Home spirometry is used to detect early changes in graft function. Bluetooth-equipped cell phones are easy to use and facilitate data transfer from home spirometry., Objective: To explore use of home spirometry with Bluetooth data transfer in outpatient lung transplant recipients., Design: Single-center prospective randomized controlled trial. Intervention-Fifty-six patients were randomized either to home spirometry with data transfer via Bluetooth-equipped cell phones or to home spirometry alone before discharge after lung transplantation. In the Bluetooth group, results were transferred to a database capable of generating alarm messages., Main Outcome Measures: Time from onset of symptoms to physician consultation during the first 6 months after lung transplantation was the primary end point., Results: Adherence to home spirometry was 97.2% in the Bluetooth group and 95.3% in the home spirometry alone group (P = .73). Median time to first consultation (P = .60) and frequency of consultation (P = .06) did not differ significantly in the 2 groups. Mean scores on the Hospital Anxiety and Depression Scale were lower in patients in the Bluetooth group (1.5; range, 0.0-4.0) than in the home spirometry alone group (4.0; range, 2.0-6.0; P = .04)., Conclusion: Home spirometry with data transfer is feasible and safe in lung transplant recipients. Compared with home spirometry alone, additional data transfer was equally effective regarding the time interval from symptom onset to consultation. Patients in the Bluetooth group reported less anxiety, which may improve emotional well-being.

Background: In the first 6 months following lung transplantation, the most frequently occurring complications are infection, acute rejection and anastomotic dysfunction. The utility of vibration response imaging (VRI) lung images in assisting with the detection of these complications was evaluated., Objectives: The study aimed to evaluate if VRI is a good, non-invasive method of detecting clinical problems in lung transplant (LTx) recipients during early follow-up., Methods: Between 06/2006 and 03/2007 all LTx patients who received transplants during the preceding 6 months at the Hannover Medical School received baseline VRI at enrollment with subsequent reassessment in combination with standard follow-up at 1, 3 and 6 months thereafter. The resulting images were analysed by two blinded reviewers., Results: Fifty-five lung transplant recipients were enrolled in the study, with 49 patients successfully completing follow-up. Device operability and patient participation occurred without significant problems. High numbers of abnormal scans were detected. According to the clinical diagnosis, 29 patients (59.2 %) were stable at all four visits. Twenty clinical problems occurred (e.g., infections, rejections, obstructions, unknown deterioration). Agreement with clinical interpretation of rejections and infections was poor. Central airway obstruction (CAO) was detected in 80% by both reviewers. Accuracy in detecting obstructions was 89%; positive predicted value and negative predicted value were 80% and 90%, respectively., Conclusion: The VRI system is a non-invasive easy-to-use method with technical success and good image quality. The high number of abnormal scans makes interpretation following LTx difficult. VRI was unable to detect deterioration in graft function with the exception of ventilation disorders like central airway complications.

Background: Patient-controlled home spirometry (HS) after lung transplantation has been shown to be valid and reliable to detect the presence of graft infection and rejection at its earliest onset. Effects of nonadherence to HS on detection of the bronchiolitis obliterans syndrome (BOS) and on graft survival are unknown., Methods: A 7-year prospective cohort study assessed nonadherence longitudinally using electronic spirometry for 24 months. During follow-up, BOS, retransplantation, and survival were stratified by adherence groups., Results: Electronic monitoring of 226 patients confirmed that 123,487 measures were performed. Period prevalence was 0.76 measures per patient day and decreased significantly over time (P<0.0001). During follow-up, BOS was developed in 32% of patients; 5% received a second transplant, and mortality rate was 19%. Kaplan-Meier event-free analysis showed decreased freedom from BOS time in nonadherers (30%) compared with good (43%) or moderate adherers (19%) (log rank 6.008; P<0.014) and a tendency toward lower retransplantation rates (log rank 3.14; P<0.07). Mantel Cox regression revealed no impact of adherence on patient survival., Conclusions: This was the first study assessing nonadherence to HS based on electronic monitoring in relation to long-term outcome after lung transplantation. Nonadherers showed decreased freedom from BOS in the largest sample to date, but did not impact survival.

Background: The impact of community-acquired respiratory virus (CARV) infections on bronchiolitis obliterans syndrome (BOS) and outcome after lung transplantation (LTx) and diagnostic techniques were prospectively evaluated., Methods: A single-center prospective cohort study was performed in LTx-outpatients between October 31, 2005 and April 30, 2006. Symptoms of respiratory tract infections were recorded and nasopharyngeal and oropharyngeal swabs were obtained. Lower respiratory sampling was performed when indicated. Immunofluorescence testing, cultures, and polymerase chain reaction for 12 different CARV were applied. Patients were followed up until December 31, 2007. New onset and BOS-stage was recorded 1 year after presentation., Results: Three hundred eighty-eight LTx-recipients were screened. Fifty-one percent reported of symptoms of respiratory tract infection. Seven hundred seventy upper and 180 lower respiratory samples were obtained. Thirty-four CARV were detected in 30 patients (7.7%): 12 parainfluenza, 7 respiratory syncytial virus, 6 metapneumovirus, 5 coronavirus, 3 rhinovirus, and 1 influenza virus. At 1 year, 43 new cases of BOS developed. One-year incidence of BOS was 25.0% in CARV-positive versus 9.0% in CARV-negative patients (log-rank P=0.01). Symptomatic CARV-infection proved to be a significant covariate for 1-year BOS-free survival in multivariate analysis (P=0.002, adjusted hazard ratio 4.13). CARV-infection did not influence BOS progression in 88 patients with prior BOS (P 0.45). After paramyxovirus infection, 8 of 24 patients developed new-onset BOS, whereas no case was recorded after rhinovirus and coronavirus infection., Discussion: Surveillance detected CARV in LTx outpatients infrequently. Symptomatic CARV-infection increases the risk for new onset of BOS, but not progression. Risk to develop BOS was especially increased after paramyxovirus infection.

Background: Flexible bronchoscopy has become an important diagnostic and therapeutic tool for the management of patients with various diseases of the chest. Availability of a 24-hour bronchoscopy service equipped with experienced personnel is becoming increasingly important especially for intensive care patients. However, such services have been implemented only in a few medical centres. The aim of this study was to evaluate the usage of a 24-hour emergency service in a large university hospital with a 1 year prospective analysis of emergency bronchoscopy service in a tertiary care centre., Methods: Frequencies, indications and efficiency of therapeutic interventions were evaluated after each bronchoscopy using a specially designed questionnaire. All bronchoscopies were performed as emergency procedures out of operational schedule. A total of 614 emergency bronchoscopies were performed, 88% of them in intensive care units., Results: The vast majority (84.5%) of the procedures were necessary for therapeutic interventions; that is, atelectasis, airway secretion, aspiration or bronchopulmonary bleeding. According to prespecified criteria, 37.6% (n = 195) of therapeutic procedures were assessed as 'very helpful' and 3.9% (n = 20) as 'life saving'. Diagnostic bronchoscopies were performed mainly to collect airway material for microbiological evaluations in immunocompromised patients. In these cases, the diagnostic yield was approximately 50%., Conclusion: The availability of a 24-hour bronchoscopy service has been found to improve patient care and was occasionally considered life saving. Thus, comparable services should be made more widely available.

Whereas sarcoidosis is characterized by an excessive inflammatory immune response mainly at the pulmonary site, circulating T lymphocytes poorly respond to antigen challenge. It has been suggested, that the extensive local inflammation might be triggered by bacterial pathogens. Recently, it has been shown that this paradoxically immunological situation likely results from a disequilibrium between effector and regulatory T lymphocytes (T(reg)). Here, we apply a DNA microarray approach in order to analyze circulating T cells for specific dysregulatory events, which should provide detailed insights in the impairment of cell-mediated immunity. Gene expression profiles were performed from peripheral blood T lymphocytes of untreated patients with pulmonary sarcoidosis (stage I) (n = 3) and a control group consisting of healthy donors (n = 3). Circulating T lymphocytes in sarcoidosis exhibit a specific gene expression pattern of molecules that are primarily involved in immune responses and lymphocyte signalling. Compared to controls patients with sarcoidosis display also alterations in gene expression of molecules with bacteriolytic and chemotactic function. Among others, array analysis resulted in increased transcript levels of Th2 immune response, whereas genes coding for molecules involved in Th1 differentiation are down-regulated. Furthermore, genes encoding proteins representing primordial antimicrobial peptides which may mobilise immunocompetent T cells and other inflammatory cells are up-regulated. This observation supports recent reports suggesting that bacterial antigens play a role in the pathogenesis of sarcoidosis. However, the results of our study indicate an unbalanced immune response towards Th2 in the peripheral blood of patients with sarcoidosis.