Long-term multicenter comparison shows equivalent efficacy of monoclonal antibodies in severe asthma therapy.

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.

Risk factors and outcomes of vocal cord paralysis after lung transplantation - a retrospective cohort study.

Vocal cord paralysis (VCP) may complicate thoracic surgery and is associated with increased morbidity and mortality. Among lung transplant (LTx) recipients, chronic pulmonary aspiration can contribute to chronic allograft dysfunction (CLAD). We herein assessed the unknown incidence and clinical impact of VCP in a large LTx cohort. All first-time bilateral LTx recipients, transplanted between January 2010 and June 2015 were included in a single-centre retrospective analysis. Bronchoscopy reports were assessed for VCP. Patients exhibiting VCP were compared to propensity score-matched negative controls regarding CLAD onset and graft survival and secondary end-points, including inpatient duration and complications; lower respiratory tract infections (LRTI) within 24 months. In total, 583/713 (82%) patients were included in the analysis. A total of 52 (8.9%) exhibited VCP, which was transient in 34/52 patients (65%), recovering after median 6 months (IQR 2-12). Compared to 268 controls, 3-year graft survival and CLAD-free survival were non-inferior in VCP [HR 0.74 (95% CI 0.35-1.57), and HR 0.74 (95% CI 0.39-1.41)] respectively. Duration of hospitalization was similar and no differences in LRTI rates or airway complications were observed. Lower pre-Tx BMI increased risk for VCP [HR 0.88 (95% CI 0.79-0.99)]. Overall, VCP did not adversely affect graft and CLAD-free survival and secondary outcomes including LRTIs and hospitalizations.

Self-reported non-adherence to immunosuppressive medication in adult lung transplant recipients-A single-center cross-sectional study.

BACKGROUND: Non-adherence to immunosuppressive treatment following solid organ transplantation is common and often associated with poorer outcomes. Non-adherence is difficult to assess, and barriers to adherence in lung transplant (LTx) recipients remain to be elucidated. METHODS: A single-center cross-sectional observational study of all LTx recipients attending our department between 07/2013 and 05/2014 was performed. Non-adherence was assessed using patient self-reporting, including Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS) along with healthcare worker (HCW) judgment and reasons for non-adherence by the Immunosuppressive Therapy Barriers Scale. RESULTS: A total of 138/504 patients (27.4%) self-reported non-adherence to immunosuppressive medication. HCW scored 96/504 patients (19.1%) as poorly adherent. Self-reported non-adherence increased with increasing interval after transplantation. The main reason for non-adherence was punctuality (75%), with only 11% reporting drug holidays. Explanations for non-adherence were primarily related to self-organization and difficulties incorporating medication into daily routine. There were no significant differences in medication knowledge or variation in trough levels. CONCLUSIONS: This study confirms that non-adherence in LTx recipients is frequent according to self-report. Barriers are self-organization and difficulties incorporating medication into daily routine. Social and behavioral support is needed to overcome non-adherence. (ClinicalTrials.gov number: NCT01889017).

DNA-based testing in lung transplant recipients with suspected non-viral lower respiratory tract infection: A prospective observational study.

BACKGROUND: Non-viral lower respiratory tract infections (LRTI) are common among lung transplant (LTx) recipients with increased mortality. Early pathogen identification is crucial to guide therapy and avoid adverse events. Results from cultures may require up to 72 hours. Multiplex polymerase chain reaction assay (PCR) may allow faster pathogen identification, but its utility in LTx recipients with suspected non-viral LRTI remains unclear. METHODS: In a prospective open-label observational trial, LTx recipients presenting with suspected LRTI received bronchoscopy with bronchoalveolar lavage (BAL). Samples were simultaneously analyzed by multiplex PCR (Curetis P55 Pneumonia) and cultures for pathogen identification. Time to result notification for PCR and cultures and time to final diagnosis were recorded. Definition of non-viral LRTI was isolation of a lung-pathogenic non-viral pathogen by either method. RESULTS: Forty-eight patients were included, with 32 (67%) having a lung-pathogenic isolate by conventional cultures. In 17/32 pathogen identification was identical on PCR, in 12/32 (37%) PCR returned negative, and in 3/32 (10%) PCR and culture identified different pathogens. Sensitivity and specificity with 95% confidence intervals for pathogen isolation for PCR were 66% (47-81) and 100% (79-100), respectively. The positive predictive value for PCR was 100% (84-100) and the negative predictive value was 59% (39-78). PCR results were available after 21.2 hours (interquartile range [IQR] 19.3-65.7) vs 23 hours (IQR 21.1-67.4) from cultures (P < .0001). The time to final diagnosis of non-viral LRTI was 22.9 hours (20.4-37.5). CONCLUSION: In LTx recipients with suspected non-viral LRTI, multiplex PCR had a lower sensitivity than cultures. Results were available 2 hours earlier.

Anti-IL-5 therapy in patients with severe eosinophilic asthma - clinical efficacy and possible criteria for treatment response.

BACKGROUND: Interleukin-5 (IL-5) antibodies represent a promising therapeutic option for patients with severe eosinophilic asthma. To date, no official treatment response criteria exist. In this study, simple criteria for treatment response applicable to all asthma patients were used to evaluate clinical efficacy and predictors for treatment response in a real-life setting. METHODS: Data from 42 patients with severe eosinophilic asthma treated with mepolizumab for at least six months were analysed. Simple criteria to assess treatment response in clinical practice were used: increase of FEV1 ≥ 12% or ≥ 200 ml, reduction of blood eosinophils (< 150/µl or < 80% from baseline) and improvement of subjective condition (patient-judged subjective improvement or worsening following therapy). Patients were considered treatment responders if two criteria were fulfilled. RESULTS: Thirty-two out of 42 patients (76% [61-87%]) were classified as responders. Within the groups (responder vs non-responder), treatment with mepolizumab led to significant increase in FEV1 (+ 600 ml vs -100 ml, p = 0.003), oxygenation (+ 8 mmHg vs -3 mmHg, p = 0.001), quality of life (visual analogue scale; + 28% vs - 5%, p = 0.004) and Asthma Control Test (+ 8 vs + 1 points, p = 0.002). In the responder group a significant decrease in the exacerbation rate over 12 months (1.45 vs 0.45, p = 0.002) was observed. Baseline characteristics (sex, BMI, smoking history, allergies, baseline level of eosinophils) did not predict treatment response. CONCLUSION: Using improvement of lung function, decrease of eosinophils and improvement of subjective condition as response criteria, 76% of treated patients could be classified as treatment responders, demonstrating the efficacy of anti-IL-5 therapy in clinical practice.

Effects of a randomized-controlled and online-supported physical activity intervention on exercise capacity, fatigue and health related quality of life in patients with post-COVID-19 syndrome.

BACKGROUND: The Post-COVID-19 syndrome (PCS), which can occur after acute respiratory syndrome coronavirus 2 infection, leads to restrictions in everyday activity. Our study assessed the impact of an online-guided intervention which intended to facilitate physical activity on the mental and physical capability of PCS patients. METHODS: We randomized 62 patients with PCS (20 male/ 42 female; age: 46 ± 12 years; body mass index: 28.7 ± 6.7 kg/m2) with a score ≥ 22 in the fatigue assessment scale (FAS) to a 3-month exercise-focused intervention (IG n = 30) or control period (CG n = 32). We assessed changes in exercise capacity (bicycle exercise test with measurements of gas exchange), fatigue, markers of health-related quality of life (HrQoL) and mental health. RESULTS: The FAS score decreased significantly in both study groups (IG: 35.1 ± 7.4 to 31.8 ± 8.5 points; CG: 35.6 ± 7.4 to 32.6 ± 7.5 points, both p < 0.01). Exercise capacity did not increase in the CG or IG (within-group changes for IG: peak oxygen uptake: 0.9 ± 2.6 ml/min/kg, p = 0.098; peak power output: 6.1 ± 17.8 W, p = 0.076) with no significant changes in HrQoL and work ability. Patients with a FAS score at baseline ≥ 35 (severe fatigue) showed no change in exercise capacity with the 3-month intervention whereas the sub-group of patients with FAS < 35 points (moderate fatigue) showed improvements, independent of the study group. CONCLUSIONS: Our 3-month intervention seems appropriate for patients with moderate fatigue, whereas those with more severe fatigue appear to be too restricted with respect to their mental or physical health status to perform exercise at a level which is sufficient to improve markers of physical performance. TRIAL REGISTRATION: German Clinical Trials Register (registration trial number: DRKS00026245) on September 2 2021.

Influence of anti-interleukin (IL)-5/anti-IL-5 receptor-α treatment on work productivity in patients with severe eosinophilic asthma.

This retrospective study shows that treatment with anti-eosinophilic antibodies in patients with severe eosinophilic asthma is associated with an increase in work productivity and a decrease in missed days at work https://bit.ly/3IIPppR.

The impact of anti-eosinophilic therapy on exercise capacity and inspiratory muscle strength in patients with severe asthma.

Introduction: Exercise limitation is frequently described among asthmatic patients and could be related to different mechanisms of the pulmonary, cardiovascular and muscular systems. Despite this, cardiopulmonary exercise testing (CPET) does not have an established role in the management of severe asthma. The aim of our study was to investigate the role of CPET and inspiratory pressure measurement in exercise capacity and muscle strength in severe asthmatic patients treated with anti-IL-5 therapy. Methods: A monocentric observational study was conducted at Hanover Medical School, Germany, from April 2018 to June 2019. Patients affected by severe asthma treated with either mepolizumab or benralizumab were included. All patients underwent CPET before the initiation of antibody therapy and after 3 months, and follow-up visits were scheduled at 3, 6 and 12 months with plethysmography, inspiratory pressure measurement and blood gas analysis. Results: 14 patients were enrolled: 10 (71.4%) females, median age 52 years (IQR 47-61). Seven patients were treated with benralizumab, seven with mepolizumab. Oxygen uptake (V'O2 peak) did not change significantly after 3 months of antibody treatment, while the mean value of the breathing reserve exhaustion reduced significantly from 78% to 60% (p=0.004). Whereas at baseline seven patients depleted the breathing reserve and two of them experienced oxygen desaturation during exercise, at 3 months no one presented any desaturation or breathing reserve exhaustion. The inspiratory pressure remained unchanged before and after the antibody therapy. Conclusion: CPET could show hints of alveolar recruitment and ventilatory efficiency in severe asthma patients treated with antibody therapy.

Post-COVID-19 syndrome: Physical capacity, fatigue and quality of life.

PURPOSE: Post-Covid-19 syndrome is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The most common symptoms include reduced exercise tolerance and capacity, fatigue, neurocognitive problems, muscle pain and dyspnea. The aim of our work was to investigate exercise capacity and markers of subjective wellbeing and their independent relation to post-COVID-19 syndrome. PATIENTS AND METHODS: We examined a total of 69 patients with post-COVID-19 syndrome (23 male/46 female; age 46±12 years; BMI 28.9±6.6 kg/m2) with fatigue and a score ≥22 in the Fatigue Assessment Scale (FAS). We assessed exercise capacity on a cycle ergometer, a 6-minute walk test, the extent of fatigue (FAS), markers of health-related quality of life (SF-36 questionnaire) and mental health (HADS). RESULTS: On average the Fatigue Assessment Scale was 35.0±7.4 points. Compared with normative values the VO2max/kg was reduced by 8.6±5.8 ml/min/kg (27.7%), the 6MWT by 71±96 m (11.9%), the health-related quality of life physical component score by 15.0±9.0 points (29.9%) and the mental component score by 10.6±12.8 points (20.6%). Subdivided into mild fatigue (FAS score 22-34) and severe fatigue (FAS score ≥35), patients with severe fatigue showed a significant reduction of the 6-minute walk test by 64±165 m (p<0.01) and the health-related quality of life physical component score by 5.8±17.2 points (p = 0.01). In multiple regression analysis age (ß = -0.24, p = 0.02), sex (ß = 0.22, p = 0.03), mental (ß = -0.51, p<0.01) and physical (ß = -0.44, p<0.01) health-related quality of life and by trend the 6-minute walk test (ß = -0.22, p = 0.07) were associated with the FAS. CONCLUSION: Patients with post-COVID-19 syndrome show reduced maximal and submaximal physical performance as well as limitations in quality of life, particularly pronounced in the physical components. These results are essentially influenced by the severity of fatigue and implicating the need for targeted treatments.

Relationship Between the Response to Antibody Therapy and Symptoms of Depression and Anxiety Disorders in Patients with Severe Asthma.

Purpose: Asthma is associated with a high prevalence of psychopathological disorders, especially depressive disorders or anxiety. In patients with uncontrolled severe asthma, monoclonal antibody (mAb)-therapy positively influenced control of mental disorders. Therefore, we evaluated the impact of antibody therapy on the burden of these mental diseases depending on responder status. Patients and Methods: Data were collected retrospectively in patients with uncontrolled severe asthma (n = 82) prior to mAb-therapy ("baseline") (omalizumab, dupilumab, benralizumab or mepolizumab). Symptoms of Major Depressive Disorder (MDD) or General Anxiety Disorder (GAD) were detected at baseline using the Hospital Anxiety and Depression Scale (HADS), as well as general sociodemographic data and lung function parameters. At 6-month (±3 month) follow-up, the burden of psychopathological symptoms under mAb-therapy was assessed using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder Scale-2 (GAD-2). Response status was classified using the Biologics Asthma Response Score (BARS), assessing exacerbations, oral corticosteroid usage and asthma control test (ACT) score. Predictors for non-response to mAb-therapy were identified using linear regression analysis. Results: Patients with severe asthma suffered from symptoms of MDD/GAD more often compared to the general population, with a higher prevalence among mAb therapy non-responders. mAb-responders exhibited a declining burden of MDD, better quality of life (QoL), less exacerbations, better lung function and better disease control compared to non-responders. A history of symptoms of depression was identified as a predictor for non-response to mAb-therapy. Conclusion: Asthma symptoms and psychological problems are linked and more prevalent in our cohort of severe asthma patients than in the general population. Patients with signs of MDD/GAD before mAb-therapy show less mAb therapy response suggesting a negative impact of prior psychological problems on treatment response. In some patients, the score on MDD/GAD was caused by severe asthma - here symptoms decreased after effective treatment.

Eosinophilic cationic protein as marker for response to antibody therapy in severe asthma.

This study of the eosinophil cationic protein (ECP) as predictor of clinical response to biological therapy in severe asthma found that ECP is not useful in unselected patients but may have a role in those not exposed to oral corticosteroids. https://bit.ly/398RwEk.

Treatment with interleukin (IL)-5/IL-5 receptor antibodies in patients with severe eosinophilic asthma and COPD.

Background: Anti-eosinophilic therapy with interleukin-5/interleukin-5-receptor antibodies represents an established treatment for patients with severe eosinophilic asthma (SEA) but did not show clinical efficacy in patients with COPD. The objective of the present study was to evaluate treatment response to anti-eosinophilic antibody therapy in patients with asthma and COPD. Methods: A retrospective comparison of pulmonary function testing, oral corticosteroid intake, quality of life and pulmonary symptom control in patients with SEA and COPD and 1:1 propensity score matched patients suffering from SEA alone was performed. All patients received treatment with either mepolizumab or benralizumab. Data were assessed prior to antibody treatment start and after 6 months of therapy. Results: Data from 84 patients (42 patients with SEA and COPD and 42 patients with SEA) were analysed. After 6 months of treatment, patients in both groups showed improved forced expiratory volume in 1 s (improvement by 11% (IQR 5-18) in the SEA and COPD group versus 15% (IQR -3-23); p=0.637) and decreased oral corticosteroid dosages (median reduction by 3 mg in the SEA and COPD group versus 5 mg; p=0.070), without significant differences between groups. Pulmonary symptom control and quality of life improved in both groups. A significant decrease in eosinophils could be measured in both groups with similar cell numbers prior to treatment initiation (600 cells·µL-1 in the SEA and COPD group versus 500 cells·µL-1). Conclusion: Anti-eosinophilic therapy with interleukin-5/interleukin-5-receptor antibodies shows clinical efficacy in patients with SEA and COPD comparable to treatment response in patients with SEA alone.

Graphic narrative based informed consent for bronchoscopy improves satisfaction in patients after lung-transplantation: A randomized controlled trial.

OBJECTIVE: This study investigated the effects of supplementing standard informed consent (IC) with a graphic narrative on patient satisfaction, periprocedural anxiety and experience. METHODS: Patients due to undergo first conscious surveillance bronchoscopy following lung transplantation were randomized to receive IC with (intervention group) or without (control group) a graphic narrative illustrating the procedure. The primary endpoint was overall patient satisfaction with the IC. Key secondary endpoints were change in state anxiety level, as measured by State Trait Anxiety Inventory, and a questionnaire assessing satisfaction with IC and adverse experience during bronchoscopy (judged by patient and examiners). RESULTS: Sixty patients were randomized, and 59 patients were included in the analysis (30 intervention-group; 29 control-group). Overall patient satisfaction was higher in the intervention group 9.5 (25Q-75Q: 8.6-9.8) vs. 8.6 (25Q-75Q: 8.1-9.2), p = 0.028). Change in state anxiety level (before vs after informed consent) was similar between the groups. There were no significant differences in adverse experience during bronchoscopy. CONCLUSION: Addition of a graphic narrative illustrating bronchoscopy improved patient satisfaction with IC but did not influence anxiety before and adverse experience during the procedure. PRACTICE IMPLICATIONS: Supplementing the IC process with a procedure-specific graphic narrative may be a simple tool to improve patient satisfaction.

Overall Response to Anti-IL-5/Anti-IL5-Rα Treatment in Severe Asthma Does Not Depend on Initial Bronchodilator Responsiveness.

BACKGROUND: Positive bronchodilator responsiveness (BDR) (change in forced expiratory volume in 1 second [ΔFEV1] ≥ +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, FEV1 improved significantly in both groups compared with baseline (P < .0001), with no significant difference between patients with positive and negative BDR (ΔFEV1 +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.

Detection of Post-COVID-19 Patients Using Medical Scent Detection Dogs-A Pilot Study.

There is a growing number of COVID-19 patients experiencing long-term symptoms months after their acute SARS-CoV-2 infection. Previous research proved dogs' ability to detect acute SARS-CoV-2 infections, but has not yet shown if dogs also indicate samples of patients with post-COVID-19 condition (Long COVID). Nine dogs, previously trained to detect samples of acute COVID-19 patients, were confronted with samples of Long COVID patients in two testing scenarios. In test scenario I (samples of acute COVID-19 vs. Long COVID) dogs achieved a mean sensitivity (for acute COVID-19) of 86.7% (95%CI: 75.4-98.0%) and a specificity of 95.8% (95%CI: 92.5-99.0%). When dogs were confronted with Long COVID and negative control samples in scenario IIa, dogs achieved a mean sensitivity (for Long COVID) of 94.4 (95%CI: 70.5-100.0%) and a specificity of 96.1% (95%CI: 87.6-100.0%). In comparison, when acute SARS-CoV-2 positive samples and negative control samples were comparatively presented (scenario IIb), a mean sensitivity of 86.9 (95%CI: 55.7-100.0%) and a specificity of 88.1% (95%CI: 82.7-93.6%) was attained. This pilot study supports the hypothesis of volatile organic compounds (VOCs) being long-term present after the initial infection in post-COVID-19 patients. Detection dogs, trained with samples of acute COVID-19 patients, also identified samples of Long COVID patients with a high sensitivity when presented next to samples of healthy individuals. This data may be used for further studies evaluating the pathophysiology underlying Long COVID and the composition of specific VOC-patterns released by SARS-CoV-2 infected patients throughout the course of this complex disease.

Canine real-time detection of SARS-CoV-2 infections in the context of a mass screening event.

INTRODUCTION: Previous research demonstrated that medical scent detection dogs have the ability to distinguish SARS-CoV-2 positive from negative samples with high diagnostic accuracy. To deploy these dogs as a reliable screening method, it is mandatory to examine if canines maintain their high diagnostic accuracy in real-life screening settings. We conducted a study to evaluate the performance of medical scent detection dogs under real-life circumstances. METHODS: Eight dogs were trained to detect SARS-CoV-2 RT-qPCR-positive samples. Four concerts with a total of 2802 participants were held to evaluate canines' performance in screening individuals for SARS-CoV-2 infection. Sweat samples were taken from all participants and presented in a line-up setting. In addition, every participant had been tested with a SARS-CoV-2 specific rapid antigen test and a RT-qPCR and they provided information regarding age, sex, vaccination status and medical disease history. The participants' infection status was unknown at the time of canine testing. Safety measures such as mask wearing and distance keeping were ensured. RESULTS: The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% (95% CI 99.74% to 99.99%) and a sensitivity of 81.58% (95% CI 66.58% to 90.78%), respectively. The overall rate of concordant results was 99.68%. The majority of the study population was vaccinated with varying vaccines and vaccination schemes, while several participants had chronic diseases and were under chronic medication. This did not influence dogs' decisions. CONCLUSION: Our results demonstrate that SARS-CoV-2 scent detection dogs achieved high diagnostic accuracy in a real-life scenario. The vaccination status, previous SARS-CoV-2 infection, chronic disease and medication of the participants did not influence the performance of the dogs in detecting the acute infection. This indicates that dogs provide a fast and reliable screening option for public events in which high-throughput screening is required.

Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions.

Although fumaric acid esters (FAE) have a decade-long firm place in the therapeutic armamentarium for psoriasis, their pleiotropic mode of action is not yet fully understood. While most previous studies have focused on the effects of FAE on leucocytes, we have addressed their activity on macro- and microvascular endothelial cells. As detected both on mRNA and protein levels, dimethylfumarate effected a profound reduction of TNFα-induced expression of E-selectin (CD62E), ICAM-1 (CD54) and VCAM-1 (CD106) on two different endothelial cell populations in a concentration-dependent manner. This reduction of several endothelial adhesion molecules was accompanied by a dramatic diminution of both rolling and firm adhesive interactions between endothelial cells and lymphocytes in a dynamic flow chamber system. Dimethylfumarate, at a concentration of 50 µm, reduced lymphocyte rolling on endothelial cells by 85.9% (P<0.001 compared to untreated controls), and it diminished the number of adherent cells by 88% (P<0.001). In contrast, monomethylfumarate (MMF) influenced neither surface expression of adhesion molecules nor interactions between endothelial cells and lymphocytes. These observations demonstrate that endothelial cells, in addition to the known effects on leucocytes, undergo profound functional changes in response to dimethylfumarate. These changes are accompanied by severely impaired dynamic interactions with lymphocytes, which constitute the critical initial step of leucocyte recruitment to inflamed tissues in psoriasis and other TNF-related inflammatory disorders.

Real-World Multicenter Experience with Mepolizumab and Benralizumab in the Treatment of Uncontrolled Severe Eosinophilic Asthma Over 12 Months.

PURPOSE: Treatment of severe eosinophilic asthma (SEA) has been revolutionized by the development of monoclonal antibodies targeting underlying immunological pathways of eosinophilic asthma. Two of the most frequently used antibodies in clinical practice are mepolizumab, targeting interleukin (IL) 5 and benralizumab, targeting the IL5 receptor alpha. The comparative treatment efficacy of these antibodies remains unclear, particularly regarding long-term outcomes. PATIENTS AND METHODS: In this multicenter, retrospective study, we included 123 patients treated with mepolizumab and 64 patients treated with benralizumab for 12 months at one of three study sites in Germany. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes in pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels. RESULTS: Both mepolizumab and benralizumab led to significant improvements in PF with an increase in median forced expiratory volume (FEV1) after 12 months from 59% to 74% for mepolizumab and 63% to 72% for benralizumab. Treatment also led to significant improvements in ACT scores after 12 months (mepolizumab: 13 [interquartile range (IQR) 9-17] to 19 [IQR 15-23]; benralizumab: 12 [IQR 9-16] to 22 [IQR 16-25]) as well as a reduction of mean OCS dose (mepolizumab 8 mg [IQR 5-12.5 mg] median prednisolone equivalent at baseline to 5 mg [IQR 3-7.5 mg]; benralizumab 7.5 mg [IQR 5-15 mg] to 5 mg [IQR 2-10 mg]). The exacerbation rates were reduced significantly, irrespective of the treatment. Overall, changes were similar after 6 and 12 months of therapy. CONCLUSION: Both mepolizumab and benralizumab are highly effective in the long-term treatment of SEA, with no clinically relevant differences in outcomes after 12 months of therapy. In both groups, improvements were similar after 6 and 12 months of therapy, underlining the feasibility of early treatment evaluation.

Generation of a NKX2.1 - p63 double transgenic knock-in reporter cell line from human induced pluripotent stem cells (MHHi006-A-4).

Tumor protein p63 (p63) encodes for a transcription factor of the p53 family and is a marker for respiratory basal cells. Based on a NKX2.1 knock-in reporter cell line from human induced pluripotent stem cells (hiPSCs) (MHHi06-A-2) we established a NKX2.1/p63 double transgenic knock-in reporter cell line using TALEN technology. The reporter enables the optimization and monitoring of hiPSC differentiation towards NKX2.1/p63 double positive cells as well as enrichment for single or double positive cells.